38722694 Brain Chemistry and Central Nervous System Drugs

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Brain Chemistry and Central Nervous System Drugs

R . 1. Brinkworth, E. J. Lloyd, and P. R . Andrews

Schoo l of Pharmaceutical Chemistry, Victorian College of Pharmacy L td., 38 1 Roya l Parade, Parkvil le,Victor ia, Aust ra l ia 3052

12

2.12.22.32.4

2.52.6

2.72.82.9

2.103

3.1

3.23.33.4

3.53.645

Introduction

The Biological Basis of Action of CNS Drugs

Neurotransmitters

Neuropeptides and Neurotransmitters in the Brain

Coexistence of Neurotransmitters and Neuropeptides

Receptors

Receptor Mechanisms

Localization of Neuropeptides and of Neuropeptide

Receptors in the Brain

Receptor Sub-types

CNS Drugs Acting at Neuroreceptors

A Common Structural Model for Compounds Active

at Brain Receptors

The Evolution of Neurotransmitters

Discovery of CNS Drugs

Ethnopharmacology

Medicinal Plants

Toxic Substances

Analogues of Endogenous Molecules

Synthetic Compounds

Drug Design

Conclusion

References

1 Introduct ion

Substances affecting the central nervous system (CNS, i .e . the

brain and spinal cord) have been known since antiquity, but

only within the past 150 years have the principles that are

needed to understand their action been established. Underlying

these principles has been the development of our knowledge

the functional anatomy of the CNS;

different classes of nerve cells ( i .e . neurons) and the

mechanisms of neurotransmission ;

causal relationships between disease states and neuronal

pathways ;

techniques for the study of the biochemistry and pharma-

cology of neurons ;

techniques to extract and characterize the pure substances

that produce psychotropic effects;

the chemistry of drugs and of their interaction with

biological systems and macromolecules; and

the principles of genetic engineering.

Consequently; much new information is-available tha t could be

used in the rational design of new drugs with greater

potency (therefore lower doses are needed) and specificity

(hence less side-effects), in contrast to older methods involving

the random screening of synthetic and natural products.

The purpose of this review is to outline some of the biological

and chemical aspects that are important for our understanding

of brain function in relation to current methods for the design

of CNS drugs.

2 The Biological Basis of Action of CNS

Drugs

The brain is an exceedingly complex organ, and it has only been

in comparatively recent times that increasingly sophisticated

techniques have enabled us to understand some of the chemical

processes which occur within it at more than a superficial level.

Laboratory methods (such as receptor-binding studies with

radiolabelled ligands, autoradiography, positron-emission

tomography, immunohistochemistry, and studies on ion chan-

nels) have greatly added to our knowledge of brain chemistry,

but at the same time have shown that there is a lot more

information still to be discovered. The answer to the question

of how the brain is organized depends very much on the

discipline of the particular researcher of whom the question is

asked: it can be described on a neurochemical, electrophysio-

logical, anatomical, functional, or phylogenetic basis. In this

review, the neurochemical organization of the brain will be

emphasized, although the other organizational bases will be

described when appropriate.

2.1 Neurotransmitters

Transmission of a nerve impulse along the axon of a neuron is

in the form of a wave of depolarization. This is caused by a

change in the ion permeability of the axonal membrane, which

results in the transfer of sodium ions into the axon from the

exterior and of potassium ions out of the axon. When the

impulse reaches the vicinity of the nerve-ending, calcium ions

move into the cell through voltage-regulated Ca2+channels.

This in turn triggers the release of a neurotransmitter into the

short gap (20-50 nm), known as the synapse, between the two

neurons. These events are shown in Figure 1.' The subsequent

binding of neurotransmitters to receptors on the adjacent

neuron will be covered in a later Section. The underlying

mechanisms of chemical communication, whether neuronal,

hormonal, or pheromonal, are essentially the same, and the

distinctions between these apparently different processes chiefly

relate to the distance over which the chemical signal has to

act.

By definition, hormones are chemical transmitters which are

carried by the circulatory system from the endocrine glands to

target cells. Neurotransmitters, on the other hand, are carried

only a short distance, by diffusion, to their target cells.2

Pheromones, such as insect sex attractants, are transmitted

through air or water from one organism to another.2 For a

substance to be classified as a bonaf ide neurotransmitter, a

number of clearly defined criteria must be met.3s4By consensus,

these are as follows.The substance must be present in the presynaptic elements

of nerve cells.

Precursors and biosynthetic enzymes must be present in the

nerve cell, usually close to the site of their presumed

action.

Stimulation of neurons should cause release of the substance

in physiologically significant amounts.

Direct application of the substance should produce re-

sponses that are identical to those caused by presynaptic

nerve cells.

There should be specific receptors in the postsynaptic

region that interact with the substance.

Interaction of the substance with its receptor should induce

changes in the ion permeability of the postsynaptic

membrane, leading to excitatory or inhibitory postsynaptic

potentials (increasing or decreasing the likelihood that the

cell will fire).

36 3

P u b l i s h e d o n 0

1 J a n u a r y 1 9 8 8 o n h t t p : / / p u b s . r s c . o r g | d o i : 1 0 . 1 0 3 9 / N P 9 8 8 0 5 0 0 3 6 3

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36 4 NATURAL PRODUCT REPORTS, 1988

ylation

Direction of

nervous impulse

Figure 1 Events involving neurotransmitters at the synapse.

(7) Specific inactivating mechanisms should exist by whichinteractions of the substance with its receptor are halted ina physiologically reasonable time.

Ever since the 1920s, when Sir Henry Dale demonstratedthat acetylcholine is a neurotransmitter, the number ofsubstances that have been shown to be neurotransmitters hassteadily increased (Table 1). Neurotransmitters may be groupedinto three classes: monoamines, amino acids, and peptides.Adenosine also appears to be a neurotransmitter, whilst other

substances (such as prostaglandins and steroid hormones) mayeventually be included. Some pharmacologically active mono-amines, such as octopamine, tryptamine,and phenethylamine,have not yet been shown conclusively to be neurotransmittersin mammalian nervous systems.

Substances in the monoamine and amino-acid classes areknown as the ‘classical’ and ‘canonical ’ neurotransmitters,and it was generally believed that any new candidate would fallinto one of these classes. This situation changed in the 1970’swith the discovery of peptides that act as neurotransmitters orneuromodulators.

Sub-classification of the neurotransmitter groupings can bemade on a structural or a functional basis. Amino acidtransmitters can be classified into inhibitory or excitatoryamino acids, depending on their effects on neuronal trans-

mission. Glutamate, which is the archetypal excitatory aminoacid, binds to receptors that are linked to Na’ ion channels, andaspartate apparently acts in the same fashion. The influx ofsodium ions causes the neuron to become depolarized; this

Table 1

MonoaminesCatecholamines Other

Noradrenaline 5-Hydroxytryptamine (serotonin)Adrenaline HistamineDopamine Acetylcholine”

Amino acids

Excitatory inhibitoryGlutamate y-Aminobutyric acid (GABA)Aspartate Glycine

Taurine

Peptidesb Purines

VIP AdenosineCCKNeurotensinSubstance PEnkephalinsEndorphinsACTHOxytocinVasopressinSomatostatinTRH

Neuropeptide Y

Neurotransmitter substances in mammalian brain

(a) Sometimes grouped by itself. (b) For a full list, see Table 2.



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NATURAL PRODUCT REPORTS, 1988-R. I. BRINKWORTH, E. J. LLOYD AND P. R. ANDREWS 365

process initiates the molecular events of neuronal transmission.

The inhibitory amino acid GABA (4-aminobutyric acid), on

the other hand, has receptors linked to chloride-ion channels.

The influx of chloride ions into a nerve cell makes it resistant

to e~citat ion.~lycine and taurine are also inhibitory amino

Classifying the monoamines noradrenaline, adrenaline, and

dopamine as ‘ atecholamines ’ not only reflects a common

structural basis but also a common biosynthetic route fromL-dopa.

2.2 Neuropeptides and Neurotransmitters in the Brain

Amongst the first neuropeptides to be discovered were substance

P, by Leeman and co-workers,8 and the enkephalins, by

Hughes, Kosterlitz, and other^.^ Since the mid- 1970’s there has

been a marked increase in the number of neuropeptides and

potential neuropeptides, and it is believed by some that the

total number may exceed 200.’ Several excellent reviews have

been published.

Neuropeptides are usually divided into classes which reflect

their originally defined roles as endocrine hormones. Of more

relevance to neurochemistry is a classification based on the

relative concentrations of neuropeptides or neuropeptidereceptors in various regions of the central nervous s y ~ t e m ~ ~ ’ ’ ~

(Table 2). On this basis, there are three broad classes, with no

two having precisely the same distribution :

(1) those whose highest concentrations occur in the cerebral

cortex, generally in small ‘ nterneurons ’ (VIP and CCK,) ;

(2) those for which the highest concentrations are in the spinalcord, medulla oblongata, and pons (enkephalins, neuro-

tensin, and substance P);(3 ) those whose highest concentrations exist in the hypothala-

mic nuclei (most of the remainder).

Some of the more recently discovered neuropeptides are

discussed in Section 2.8.In general, the locations of neuropeptides in individual

neurons have been demonstrated by means of immunohisto-

chemical techniques; a second antibody, coupled to somefluorescent compound, is frequently used. Since the presence of

neuropeptides is demonstrated indirectly by immunochemical

Locations of neuropeptides in the mammalian

Highest concentration in the cerebral cortexVasoactive intestinal polypeptide (VIP)Cholecystokinin (CCK)

Highest concentration in midbrain, hindbrain,and spinal cord

Neurotensin (NT)Substance P (SP)Enkephalins (ENK)

Dynorphins (DYN)Endorphins (END)

Highest concentration in hypo halamusAdrenocorticotropic hormone (ACTH)Oxytocin (OXT)Vasopressin (AVP)

Luteinizing-hormone-releasing ormone (LHRH)Somatostatin (SST)Thyrotropin-releasing hormone (TRH)Corticotropin-releasing factor (CRF)Angiotensin I1a-Melanocyte-stimulating hormone (a-MSH)BradykininNeuropeptide Y (NPY)Bombesin (BN)Galanin (GAL)

Calcitonin-gene-related peptide (CGRP)Atrial natriuretic peptide (ANP)Diazepam binding inhibitor (DBI)

techniques, terms such as ‘neuropeptide-like ’or ‘neuropeptide

immunoreactive’ are used. Figure 2 shows a simplified

representation of the human brain in longitudinal section and

various transverse sections are shown in Figure 3; he various

regions and cell groupings that are mentioned in this review are

identified in these Figures. A comprehensive review by Palkovits

of the localization of peptides in the central nervous system was

published in 1985.16

The work of Dahlstrom and Fuxe” established an ‘ABC’nomenclature for groups of neurons in the hind-brain and the

mid-brain of the rat whose projections extend into regions of

the mid-brain and forebrain (such as the basal ganglia,

thalamus, hypothalamus, and other parts of the limbic system)

respectively and into the cerebral cortex.

A relatively simple system in the CNS which illustrates the

multiplicity of neurotransmitters in central neurons is the pain-

perception (algesia)/pain-control (analgesia) system (Figure 4).

Cellsof the dorsal root ganglia produce substance P, along with

other neuropeptides, and these neurons pass the pain stimulus

to the dorsal horn of the spinal cord. Neurons of the lateral

spinothalamic tract carry these messages to the posterolateral

nucleus of the thalamus, presumably using acetylcholine as a

neurotransmitter, with further connections to the cerebral

cortex. Pain control is carried out by inhibiting the productionof enkephalins and other peptides in the interneurons in the

dorsal horn and by the descending pathway, which consists of

5-hydroxytryptamine (5-HT), substance P, thyrotropin-releas-

ing hormone (TRH), and enkephalin-producing neurons. The

periaqueductal grey and the large raphe nuclei act as relay

centres.15. a

2.3 Coexistence of Neurotransmitters and Neuropeptides

The term “Dale’s principle” has come to mean the idea that

one neuron can only produce one type of neurotransmitter.

However, Dale actually proposed that all synapses of a single

neuron act by the same chemical transmission mechanism,which could cover more than one neurotransmitter.19 Evidence

has now been accumulated by Hokfelt, Lundberg, and othersthat many neurons secrete both a classical neurotransmitter

and a ne~ropeptide. ’~able 3 lists some of the known associa-

t i o n ~ . ~ ~ - ~ ~

All aspects of coexistence that were then known were

reviewed at a conference in Stockholm in 1985.24 The

implications of coexistence are still mostly speculative, although

a number of generalizations can now be made, including the

differential response of classical neurotransmitters and neuro-

peptides to the frequency of stimulation, more complex

autoregulation, and synergistic effects.25The release of neuro-

peptides seems to require a higher frequency of stimulation

than does the release of classical neurotransmitters. At this

level, inhibitory processes (such as down-regulation via auto-

receptors) begin to reduce the release of classical neurotrans-

mitters. The mechanism of action of autoreceptors appears toinvolve inhibition of Ca2+-mediatedneurotransmitter release,

implying that autoreceptor-mediated regulation will involve all

coexistent neurotransmitters at a particular synapse. Synergistic

effects have been demonstrated for a number of receptors of

coexistent neurotransmitter pairs, including VIP/acetylcholine,

substance P/5-HT, and neuropeptide Y/noradrenaline. 25

2.4 Receptors

For the purposes of this review, a receptor will be defined as a

membrane-bound protein or protein complex which specifically

binds a neurotransmitter, a drug, or a hormone. Recent reviews

on receptor^^^-^' have listed the requirements for a bona$dereceptor as follows:

(1) the binding of the ligand is saturable, indicating that there

(2) the binding is reversible;

is a finite number of receptors;

(3 ) the binding exhibits specificity and selectivity;



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366 NATURAL PRODUCT REPORTS, 1988

St r i a Te,rminalis

"

Figure 2 Longitudinal sections of the human brain through the mid-line, with the various regions projected onto the plane of the mid-line, showing

the following regions: A cerebral cortex, B olfactory bulb, C orebrain and septa1 nuclei, D bed nucleus of stria terminalis, E basal nucleus of

Meynert, F hypothalamic nuclei, G amygdala, H hippocampus, I posterior pituitary, J caudate nucleus, K putamen, L globus pallidus, M

thalamus, N substantia nigra, 0 habenular nuclei, P superior colliculus, Q inferior colliculus, R dorsal raphe nucleus, S periaqueductal grey, Tcerebellum, U pons, V locus coeruleus, W large raphe nucleus, X nucleus of solitary tract, Y dorsal nucleus of vagus nerve, Z substantia gelatinosa.

For clarity, some regions are not shown on both (a) and (b). The labels (i)-(vi) in (b) refer to positions of the transverse sections in Figure 3.

Based on reference 15 .



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NA TU RA L PRODU CT REPORTS, 1988-R. I. BRINKWORTH, E. J. L L O YD A N D P. R . A N D R E WS 367

I i ) ReticularFormation

InferiorOlivary Nucleus

Red Nucleus NI

~ Corm s Callosum

(v )

( iv ) Corpus Caiiosum

\ J

-Anterior Commisure

Figure 3 Transverse sections of the human brain at the positions as indicated by (i), (ii), etc . in Figure 2b. Identifying labels A, B e t c . are as inFigure 2. Based on reference 18.

(4) there is a correlation of binding with the activity of

agonists, as measured by dose-response curves;

(5) there is a correlation between the distribution of its binding

in a tissue (or sub-cellular sites) and the known localization

(or target site) of the ligand.

The term ' igand'here refers to a small molecule (a neurotrans-

mitter, a drug, or a hormone) which binds to a receptor. In thiscontext, an agonist is defined as a compound which binds to a

receptor and triggers a physiological response. Virtually all

neurotransmitters and hormones are agonists. An antagonist,

on the other hand, binds to a receptor but does not trigger a

response. Antagonists block the action of agonists.

Two mechanisms have been proposed to explain the binding

of antagonists and agonists to receptors. The concerted model

involves equilibrium between two conformational states, these

being the agonist conformation and the antagonist conforma-

tion. The ligand has a preference for one of these states, therebyshifting the equilibrium. 8 In the sequential or induced-fit

model, on the other hand, the transition between the agonist

and antagonist states is induced by the binding of the ligand.29



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Cerebral Cortex

Nuclei

HistamineLHRHOx y oc n

VasopressinA C T H

EndorphinM-MSH

Thalamus

..

..

A mygdala

ACh?

Angiotensin I I

Lateral SpinothalamicTract -

3*.*.. ..

,. .: *.. .’

Central G rey Region ofMesencephalon(Periaqueductal G rey )

Raphi! Nucleus

Neurotensin Enk ephal in

at in

Dorsal R oo t Ganglion

Mos tly Substance P, bu t also VIP, Somatostat in

CCK,. Ansiotensin I I and Dynorph in

. .‘ . _

Lateral Spirio-thalamic Tract

ZSpinal Cord

3-- Pain Contro lPain Perception

Figure 4 Pathways of perception and control of pain.

Receptor- binding studies (using radioligands) date from the

early 1970’s, when the binding of [1251]bungarotoxin toacetylcholine receptors in the electric organs of Ekctrophoruselectricus was studied by Changeux and c o - ~ o r k e r s ~ ~nd the

binding of 3H-labelled naloxone to opiate receptors in rat brain

was investigated by Pert and Snyder.31

Since then, radioligand-binding methods have been exten-

sively utilized in the study of neurotransmitters and hormones

and of the way in which these substances interact with their

respective receptors. For more detailed discussions of this field,

consult the reviews by Carman-Kr~an~~nd Williams and

U ’ P r i ~ h a r d . ~ ~esides radioligand-binding, other methods for

studying receptors in situ include a ~to radi ogr aph y~~nd posi-

tron-emission tom~graphy.~~raphical methods such as the

Scatchard Plot,36 he Hill Plot,37and the Eadie-Hofstee Plot38

have long been available for processing results from radio-

ligand-binding experiments. More recently, iterative, non-linear regression-analysis techniques such as LIGAND~’ and

E B D A ~ ’ , ~ ~ave become available and can provide more accurate

estimates of the parameters involved.

2.5 Receptor Mechanisms

The binding of an agonist to a receptor is linked to the

production of a secondary messenger in what is known as a

transduction mechanism, with the secondary messenger in-

fluencing an effector system (usually an enzyme or an ion

channel) as shown in Figure 5 . This section describes these

events in more detail and in molecular terms.

Where the receptor is directly linked to an ion channel

(Na+,K’, Ca2+, r Cl-), subsequent events occur very quickly,

in milliseconds, whether or not the effect of the agonist is

excitatory or inhibitory. On the other hand, where the receptor

is ultimately linked to an enzyme, changes may take from

minutes to days to occur.

Considering the latter case in more detail, there are a number

of secondary messengers and primary effectors (enzymes) that

have been shown to be linked to slow-acting receptors. Thesesecondary messengers are 3’,5’-cyclic adenosine monophos-

phate (CAMP),3’,5’-cyclic guanosine monophosphate (cGMP),

1D-myo-inositol 1,4,5-trisphosphate (IPS), and diacylglycerol



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NATURAL PRODUCT REPORTS, 1988-R. I. BRINKWORTH, E. J . LLOYD AND P. R. ANDREWS 369

Transduction

MechanismReceptor

Table 3 Coexistence of neurotransmitters in the mammalian brain24

r

Secondary Effector

Messenger System

Classical Neuropeptideneurotransmitter

Brain region

Noradrenaline Enkephalin Locus coeruleusNeuropeptide Y Locus coeruleusNeuropeptide Y Medulla oblongataVasopressin Locus coeruleus

Adrenaline

Dopamine

5-HT

GABA

Acetylcholine

Neurotensin Nucleus solitariusCCK Nucleus solitariusNeuropeptide Y Medulla oblongataSubstance P Medulla oblongata

CCKNeurotensinNeurotensin

Ventral tegmentumVentral tegmen umInfundibular/arcuatenuclei of hypothalamus

Substance P Medulla oblongata

TRH Medulla oblongata

CCK Medulla oblongata

Enkephalin Medulla and pons

Somatostatin (SST) ThalamusSomatostatin (SST) HippocampusCCK CortexNeuropeptide Y CortexEnkephalin Striatal region

VIP CortexSubstance P Nucleus of dorso-lateral

Enkephalin Superior olivary body

Galanin Septa1 forebrain

(raphe nuclei)

(raphe nuclei)

(raphe nuclei)

tegmentum

(medulla)

Animal

CatRatMan, ratRat

RatRatRatRat

RatRatRat, man

Rat, cat

Rat

Rat

Cat

CatRat, cat, monkeyCat, monkeyCat, monkeyRat

RatRat

Guinea pig

Rat

Stimulus (Agonist binding)

Recognition

Figure 5 Transduction of a stimulus from a receptor to effector systems.

(DG). The structures of these compounds are shown in Figure

6 . All of these compounds are produced by membrane-bound

enzymes that are linked to the receptor by another protein,which is the ‘transducing element’. The receptors, the trans-

ducing elements, and the enzymes that are responsible for the

generation of secondary messengers probably only come

together transiently. This is the ‘floating receptor’ or ‘mobile

receptor ’hypothesis, and the implications are tha t one effector

system can be served by more than one receptor and that one

receptor type can regulate a number of membrane-bound

functions.42 Although not directly produced by a receptor-

linked enzyme, the metalloprotein complex Ca2+-calmodulin

(CaCM) is another important secondary messenger which is

linked to the IPJDG system.

3’,5’-Cyclic adenosine monophosphate, which was discovered

by Sutherland and co-workers in the 1 9 5 0 ’ ~ ’ ~ ~s responsible for

the control of many metabolic processes. It is synthesized from

ATP by a membrane-bound enzyme, adenylate cyclase, andhydrolysed to 5’-AMP by a specific phosphodiesterase. A key

role for CAMP is the activation of protein kinase A (PK-A).

This is one of a group of protein kinases which use cellular

enzymes and other proteins as substrates for phosphorylation

and which are the link in the control of metabolism by

hormones and neurotransmitters alike. A review in 1982 byC ~ h e n ~ ~ncludes a discussion of the ubiquitous nature of

protein phosphorylation in cellular control, whilst in a review

in 1984 Nestler and colleagues45defined the role of protein

kinases in neuronal tissue. Protein kinases other than PK-A

will be discussed later.

Binding of an agonist to a PK-A-linked receptor can result in

either an increase or a decrease in adenylate cyclase activity.

The difference occurs at the level of transduction, which links

the recognition step of agonist binding to activation of the

adenylate cyclase. Transduction of receptor-mediated events

occurs almost exclusively as a function of GTP-binding

proteins, known as ‘G-proteins ’, which include (i) G, (or NJ,

(ii) G, (or Ni), (iii) Go, iv) G,, (v) transducin, and (vi) R A S -protein.46 It should be noted that G-proteins are involved in all

types of ligand-receptor or stimulus-receptor interactions,including the process of olfactory reception, which is discussed

in two recent review^.^'^^^The binding of an antagonist to a receptor does not trigger



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the conformational change in that receptor that agonist bindingdoes. Hence, binding of an antagonist does not involve G-proteins. This fundamental difference was first noticed in p-adrenergic receptors by Leflcowitz and c o - ~ o r k e r s , ~ ~nddiscussed in a review in 1984. A working model was developedin which the agonist-receptor complex displaces GD P from thetransducing element and the complex is itself displaced byGTP.

A number of substances have proved to be extremely usefulas tools in the study of G-proteins. Non-hydrolysable analoguesof GTP (such as GppNHp and GppSp) have helped to establishthe role of GTP in this system. Toxins from several bacteria,namely cholera toxin and pertussis toxin, have as their mode ofaction a specific interaction with G-proteins. Aluminiumtetrafluoride anion is an inhibitor of G T P ~ S ~ , ~ Ohile thenatural product forskolin, from the plant Coleus orskohlii , canactivate adenylate cyclase in place of CAMP. The structures ofGppNHp and forskolin are shown in Figure 6.

The key features of G, (N,) and G, (Ni) have been establishedby workers such as Hildebrandt, Gilman, and others over anumber of y e a r ~ . ~ l - ~ ~hese results are summarized in a reviewby Gilman.55Both G, and Gi are trimeric proteins, containinga, p, and y subunits. The p and y subunits, with molecular

weights of 35000 and 10000 respectively, are common to bothproteins whereas the a subunits a, (mol. wt =45000) and ai(mol. wt =41000) are different proteins. Both G, and Gi bindGTP after they have been activated by the receptor-agonistcomplex, causing the G-protein to dissociate into subunits ;the a-GTP dimer binds to adenylate cyclase. The a,-GTPcomplex stimulates adenylate cyclase whilst a,-GTP inhibits it.Following this association, the GTPase activity of the a subunithydrolyses the GT P to GD P and inorganic phosphate, and thea-adenylate cyclase complex dissociates. The a-induced stimula-tion or inhibition of adenylate cyclase is therefore tran~ient.~'

3: 5'- cyclicAMP

3',5'- cyclic GMP

0

Cholera toxin is an enzyme which catalyses the adenosine-diphosphoribosylation of the a, subunit, resulting in inhibitionof its GTPase activity and thereby causing a permanentswitching-on of adenylate cyclase activity. Analogues of GT Psuch as GppNHp cannot be hydrolysed by the GTPase activity,so again the activation is prolonged. Pertussis toxin, alsoknown as islet-activating protein (IAP), has a similar effect onai s does cholera toxin on a,. In this situation, however, the

adenosine-diphosphoribosylatedai

ctually activates adenylatecyclase by an as yet unknown mechanism, although it seems tobe related to the supply of py dimers which bind to a,.54Amodel for the transduction mechanism of G, and G, isillustrated in Figure 7.32

Receptors that are linked to G, include the /3- and p,-adrenergic, adenosine-2, histamine-2, dopamine- I , 5-HT,vasopressin-2, glucagon, and ACTH. Receptors acting via G,include a,-adrenergic, adenosine- 1, p-opiate , 8-opiate, anddopamine-2.32Recently, neuropeptide Y has been added to thelist.56

Only a small number of receptors have been shown to belinked to the production of cGMP by guanylate cyclase, andthese include the muscarinic re~eptor,~'he H,-histaminereceptor,58 he CCK receptor,59 and the A NP receptor.60

Apart from adenylate cyclase and guanylate cyclase, theother key membrane-bound enzyme linked to receptors isphospholipase C (PhosC), otherwise known as phosphoinositolphosphodiesterase (PIpde). Phospholipase C catalyses thehydrolysis of I-phosphatidyl-D-myo-inositol,5-bisphosphate(PIP,) to 1,2-diacylglycerol (DG) and D-myo-inositol 1,4,5-trisphosphate (IP3). (The residues at positions 1 and 2 of DGare predominantly stearoyl and arachidonoyl, respectively.)The most comprehensive review on this subject is that byA bdel- La i f.61

Receptors are linked to PhosC by another G-protein, known

PIP,

Hm=P-OQ O=P-CP -

Fbrakolin

Phorbol Ester

Figure 6 Structures of compounds involved in transduction mechanisms. The arrow indicates where PIP, is cleaved by phospholipase C.



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NATURAL PRODUCT REPORTS, 1988-R. I. BRINKWORTH, E. J .

as G, or N,.62Like G,, G, is sensitive to pertussis t o ~ i n . ~ ~ , ~ ~he

/3 and y subunits of G, are the same as those of G, and Gi, but

the 01 subunit is different, having a molecular weight of

39000.62As well as being activated by G,-GTP, PhosC is also

activated by Ca2+ n a separate mechanism from Gp.65

The complete scheme of the functions of DG and IP,, which

both act as secondary messengers, is shown in Figure 8 . 1,2-Diacylglycerol stays in the membrane to activate another

protein kinase, protein kinase C (PK-C). The ultimate fate of

DG is its conversion into arachidonic acid, which is the

LLOYD AND P. R. ANDREWS 37 1

precursor of the prostaglandin/thromboxane seriesof bioactive

compounds. Activation of PK-C can also be carried out by a

group of compounds known as phorbol esters (see Figure 6 ) ,which are tumour-promoting.66 Phorbol esters can thus be

thought of as naturally occurring analogues of DG.

The connection of PK-C with tumorogenesis appears to

involve the ras oncogenes. The ras protein of yeast was the first

to be recognized as a G-pr~tein.~'ecent studies have linked

the phosphatidylinositol/Ca2+ system to activation of theoncogenes fos and Also required for PK-C activity is

Agonist Agonist

CAMP- ependent

Protein Kinases1

Pro e in Phosphory a on

Figure 7 Transduction mechanisms involving G, and Gi.

Agonist

Ca2+ I

Phorbol EstersGABAI I

Protein

Phosphorylation

Ca2+- CaM

- -Dependent

Kinases

Figure 8 Transduction mechanisms involving inositol phosphates and calcium.



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pho~phatidylserine.~~K-C has a molecular weight of about

77000,70 nd there are three types: a, , and y. The y type is

found in many tissues, whilsta nd P are the predominant types

in brain.71 Further aspects of PK-C may be found in a review

in 1984 by Ni s h i~ u ka .~ ~rotein kinase C is specific for serine

and threonine residues, whereas PK-A is specific for tyrosine

residues.44

Whilst the role of DG is in the activation of PK-C, IP, is

involved in calcium mobilization. The Ca2+ on is stored in thesmooth endoplasmic reticulum (smooth ER), and the normal

resting concentration of Ca2+within the cell is of the order of

0.1 pmol drn-,. IP, causes release of Ca2 + rom the smooth ER,so that its concentration rises to levels as high as 1Opmol

influx of Ca2+ rom outside the cell was not understood until

comparatively recently. Entry of Ca2+ s stimulated by myo-inositol 1,3,4,5-tetrakisphosphate IP4), which is synthesized

from IP, by a specific k i n a ~ e . ~ ~ . ~ ~obilization of the Ca2+

stores in the endoplasmic reticulum is a prerequisite for this

process, as proposed by P ~ t n e y . ~ ~

The most importan t function of Ca2+ s in the metalloprotein

Ca2+-calmodulin (Ca2+-CaM).44 This complex acts as a

secondary messenger, but can form only if cytosolic Ca2 + evels

rise to a t least 1 pmol dm-,. It is an activator for severalenzymes, which include a group of protein kinases and

adenylate k i n a ~ e . ~ ~he calmodulin molecule binds four Ca2+

ions at the micromolar

Neurotransmitter receptors which are linked to the inositol/

Ca2+system hrough phospholipase C include muscarinic acetyl-

choline, a,-adrenergic, H,-histamine, 5-HT2, vasopressin- 1,

angiotensin-11, bradykinin, and substance P.61,70

One of the most important therapeutic agents in the treatment

of manic disorders is lithium (Li+). Recent studies strongly

suggest that it interferes in the inositol-salvage process in brain

neurons by which IP, is recycled to produce new PIP,, which in

turn reduces the levels of secondary messengers in the brain.77

Calcium is an activator of the membrane-bound enzyme

phospholipase A,, which catalyses the hydrolysis of membrane

phospholipids to lyso-phospholipids and arachidonicThe latter is the precursor for prostaglandins. GABA-B

receptors may be linked to phospholipase A,.79 Another

enzyme which is activated by calcium is the protease calpain.

Lynch and co-workers have implicated calpain in the mech-

anism of long-term potentiation (LTP) in rat hippocampus,

which is of fundamental importance in the establishment of

memory.8o

The functions of the GTP-binding protein Gowere unknown

for a long time, despite the ubiquitous nature of Go,which has

been suggested as occurring in the process by which opiates and

opiate peptides inhibit the release of substance P, this being a

Ca2+-dependent rocess. Regulation of these neuronal calcium

channels appears to occur via Go.81

The stimulus acting on a receptor need not be a chemical

substance. Rhodopsin is the chemical component of the retinawhich is the primary recognition site for stimulus by light. This

membrane-bound protein is linked to a cGMP phosphodi-

esterase through another GTP-binding protein, transducin.82

Recently it was discovered that rhodopsin has a strong sequence

homology with the P-adrenergic receptor, and thus both

proteins share structural and functional such as the

location of hydrophobic membrane-binding regions.

Compounds of the benzodiazepine class, typified by diaze-

pam, are extensively used in the community as anxiolytics and

~ e d a t i v e s . ~ ~lthough benzodiazepines do not competitively

bind to GABA receptors, there is a connection. It has been

found that the binding of agonists at benzodiazepine receptors

is enhanced by agonists of GABA receptors, and vice versa.85The addition of a GABA agonist such as 10-5mo l dmP3

muscimol can enhance benzodiazepine affinity by as much as2.45-fold. The ratio of activities, with and without the GABA

agonist, is called the 'GABA ratio'.86Compounds with affinity

at benzodiazepine receptors exhibit a full spectrum of pharma-

dm-3. 2 The connection between this phenomenon and the

cological activity, from anticonvulsant to convulsant. This

spectrum is reflected in the GABA ratios, which range from

2.45 to 0.46.86 Both GABA receptors and benzodiazepine

receptors, along with barbiturate receptors, are part of one

large ' upercomplex ', involving C1- channelsa7 Benzodiaz-

epines therefore act by potentiating the inhibitory effects of

GABA on C1- channels. Antagonists of benzodiazepines, such

as Ro1788, simply block the binding of benzodiazepines

without affecting GABA activity. Inverse agonists of benzo-diazepines ( i . e . compounds for which the GABA ratio is less

than 1.0) actually prevent GABA activity and, as a result,

behave as convulsants.

Opiate receptors have been shown to be linked to ion

channels, with the analgesic activity of opiates and opiate

peptides such as enkephalins being due to an inhibitory effect

of these substances on the sensory pathways that carry pain

information and which use substance P as a neurotransmitter. lo

The p- and &opiate receptor that are located on substance P

nerve-endings, as well as causing inhibition of adenylate cyclase,

result in an outflow of K' ions.88 Neuronal activity is thereby

decreased and the release of substance P is inhibited. K-Opiate

receptors, on the other hand, are linked to the Ca2+ hannels

that are involved in translating the wave of depolarization into

the release of neurotransmitter^,^^ which also causes inhibitionof the release of substance P and hence a diminution in the

transmission of pain. Neuronal receptors share common

mechanisms of action with the whole gamut of receptors,

including hormonal, pheromonal, olfactory, and light recep-

tors. The evolutionary implications of this commonality will be

discussed in Section 2.10.

2.6 Localization of Neuropeptides and of NeuropeptideReceptors in the Brain

As has already been mentioned, the localization of neuropep-

tides in the various regions, structures, and nuclei of the brain

has been extensively studied by using a range of immunological

techniques.16 The other major way of studying the regional

Table 4 Localization of neuropeptides in the rat CNS

Neuropept de

ABCD

EFGHI

JK

LMN0

P

QRST

UVWXY

Z

II

R

-

-

I

I

-

RI, R

IR

-

RR

I

R

-

I, RI, RII

I, RI

(a ) See Figures 2 and 3. (b) See Table 2 for identification. (c) R =Receptor,

I =Immunoreactive substance.



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NATUR AL PRODUC T REPORTS, 1988-R. I. BRINKWORTH, E. J . LLOYD A ND P. R. ANDREWS 373

Table 5 Drugs acting at neuroreceptors

Therapeutic class Receptor

Neuroleptic DA2

Dopamine agonistCholinergic

Anticholinergic

Analgesic

PsychotomimeticHallucinogenicStimulant

ConvulsantAn tidepressant

Anxiolytic

D A , +D A ,Muscarinic

NicotinicMuscarinicNicotinic

P

PK

(T

5-HTCatecholamine

uptakeG1 ycineNoradrenaline

5-HT uptakeBenzodiazepine

Sedative BarbiturateAn ticonvulsan GABA

Convulsant GABAGABA

Stimulant AdenosineCalcium-channel Ca2+channel

M A 0 inhibitorAnticholinesteraseDOPA-decarboxylase

GABA-transaminase

blocker

inhibitor

inhi bit or

(a ) See Figure 9.

Chemical type Example

Butyrophenone HaloperidolPhenothiazine ChlorpromazineBenzamide Sulpiride

ApomorphineOxotremorine

NicotineAtropineTubocurarine

Benzomorphan MorphineNon-benzomorphan Fentanyl

Ti fluadomPhencyclidine

AmphetamineErgotarnine LSD

StrychnineImipramine

Benzodiazepine (BZP) D iazepamNon-BZP Zopiclone

PhenobarbitalPhenytoin

BicucullineMuscimolCaffeine

Dihydropyridine Nitrendipine

DeprenylPh ysostigmineCarbidopa

Gabaculine

importance of neuropeptides is to investigate the localization of

neuropeptide receptors. Ideally, these two areas of studyshould produce complementary results, in that neuropeptide

receptors are more likely to be found near the terminal ends of

nerve fibres that contain a neuropeptide-immunoreactive

substance. The location of neurons that contain either specific

neuropeptides or neuropeptide receptors is believed to be an

indication of the function the neuropeptide may play in CNS-regulated processes.

The localization of neuropeptide-like immunoreactivity16

and the localization of neuropeptide receptorsgo in various

parts of the mammalian brain, particularly rat brain, have been

extensively studied for such peptides as VIP, substance P, and

neurotensin. The results of these studies are described in

considerable detail in major r e ~ i e w s . ~ ~ ~ ~ ~here are a number of

polypeptides which have been shown only in comparatively

recent times to be important in the CNS. These includeneuropeptide Y, bornbesin, galanin, calcitonin-gene-related

peptide, and atrial natriuretic peptide. Table 4 summarizes the

localization of these five peptides and their receptors in the ratC'S.91-116

2.7 Receptor Sub-types

Ahlquist first recognized that a particular hormone or

neurotransmitter may bind to more than one sub-type of

receptor.l" In this case, it was the discovery of the a- and p-sub-types of the adrenaline (or noradrenaline) receptor. This

phenomenon - hat there are sub-populations of receptor types

in different tissues-has been shown to occur with many

receptors for hormones or neurotransmitters. Further sub-

division of receptor types (a1,a,, pl, p,) is often necessary,particularly if analysis of binding curves for radioligands

indicates the presence of heterogeneous populations of recep-

tors.

The distinction between receptor sub-types can be made on

a number of levels, includingThe receptor being more responsive to the 'hormonal '

form of the transmitter than to the 'neuronal', or

vice versa. The differential responses ofPI-and P,-adrenergic

receptors to adrenaline and noradrenaline is a case in

point.49

Receptor sub-types may be distinguished by the transducer

systems to which they are linked. a, (Ca2+-inositol), a2

(Gi), p, (GJ, and /?, (G,) noradrenergic receptors are so

distinguished.

Tissue distribution of receptor sub-types is often different

and usually a reflection of their function. Histamine-1

receptors are found on smooth-muscle fibres whereas

histamine-2 receptors are found on fundic mucosal cells in

the stomach.118

The affinities of agonists and antagonists at different sub-types are often different, sometimes markedly so. Very

selective antagonists with high affinity are often used (inradiolabelled form) as specific radioligands, e . g . [3H]-prazosin (a,-adrenergi~)"~ nd [3H]rauwolscine (a,-adren-

ergic).120

Only a relatively small percentage of receptors have been

isolated and their properties studied. The results indicate

that receptor sub-types are actually different proteins.

Differences range from relatively small @,- and P,-adren-

ergic12'* 22) to extremely marked (nicotinic and muscarinic

acetylcholine 23, I

It is possible that some receptor sub-types arise through

differences n their membrane components, as, for example,

in p- and &opiate receptors, which differ in their suscepti-

bility to inhibition by This may be related tothe fact that &opiate receptors lack a cerebroside sulphate

that has been shown to be a necessary component of the

p-opia te receptor

N P R



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2.8 CNS Drugs Acting at Neuroreceptors

Many classes of drugs that are active in the central nervous

system have as their mode of action their affinity for receptors,

with some acting as agonists and others as antagonists. Table

5 lists the major classes involved with neuroreceptors. Other

drugs, such as prazosin (a1)nd ketanserin (5-HT2), although

having high affinity for their respective receptors, are unable to

cross the blood-brain barrier, and their primary site of actionis in the cardiovascular system. Table 5 also lists other CNS

drugs which act at sites other than genuine neuroreceptors. The

chemical structures of these drugs are shown in Figure 9.Drugs acting at CNS receptors must possess both strong

affinity at the target receptor and specificity at that receptor

relative to other receptors. The simple but elegant graphical

technique of the receptor- binding profile, as developed by

Clo~se,’~’ rovides a way of presenting both affinity and

specificity by means of a histogram of binding affinities at

different receptors on a log scale. Figure 10 shows the receptor-binding profiles of a number of drugs with varying degrees of

specificity.

1

Q-4)6

MeN

7

HOqM eH

9 10

“Me2

11 12 13 14 15 16

17 18 19 20 21

23 24 25 26

Figure 9 Structures of drugs acting in the CNS. Names are shown in Table 5.

22

COzH

28



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NAT URA L PRODUCT REPORTS, 1988-R. I. BRINKWORTH, E. J . L LO Y D A N D P. R . A ND R E WS 375

Figure 10 Receptor-binding profiles of a number of drugs with varying degrees of specificity. These are (a) clonidine, which is an a,-adrenergic

partial agonist with some a1 ctivity; (b) mianserin, with a2, HT,, and H , activity; (c) spiperone, an antagonist with D, and 5HT2 activity;

(d) imipramine, a tricyclic antidepressant; (e) lisuride, with very broad specificity over a range of receptors ; nd (0bromocriptine, with a similar

broad specificity.

IS-?



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2.9 A Common Structural Model for Compounds Active atBrain Receptors

In a series of publications from this la b o r a t ~ r y l ~ ~ - l ~ ~e have

proposed the hypothesis that there is a common structural basis

for compounds that act in the central nervous system, whether

as a drug o r as a neurotransmitter. That is, there is a common

structural basis for al l CNS-active compounds, not just those

from within one class. Our results led us to propose that:(1) there is a common structural basis for the activity of many

different classes of CNS-active drugs;

(2) the aromatic ring and the nitrogen moieties are the primary

binding groups whose topographic arrangement is funda-

mental to the activity of these drug classes;

(3) the nature and placement of secondary binding groups,

known informally as 'foliage ', determine different classes

of CNS drug activity.

In naturally occurring neurotransmitters, whether they are

monoamines or neuropeptides, three types of aromatic ring can

be found in the 'primary aromatic binding position'. These

are as follows:

(1) Phenyl rings, including those of tyrosine and catechol-

amines. For many neuropeptides, the primary aromatic

binding site is a tyrosine residue or a phenylalanine residue.This is often determined by studying natural peptide

analogues such as morphine (see Section 3.2), or progres-

sively smaller oligopeptide fragments.

(2) Indole rings, as in serotonin or in peptides that contain

tryptophan residues.

(3 ) Imidazole, as in histamine or in peptides that contain

histidine residues. Anomalous results involving clonidine

and cimetidine have led to the suggestion that there are

' midazole-binding' sites in the brain, perhaps using

imidazoleacetic acid as the endogenous ligand. 132

2.10 The Evolution of Neurotransmitters

The major implication that can be derived from the common

pharmacophore model described in the previous section is thatthere once existed a primaeval receptor which was the ancestor

of all neurotransmitter receptors, whether monamine or

neuropeptide. On the basis of the common model, it is tempting

to speculate that the first receptor may have been specific for

phenethylamine. In any case, it is worth noting that the only

neurotransmitters which do not fit the common model are

glutamate, aspartate, GABA, glycine, taurine, adenosine, and

TRH.

When considering the evolution of receptors and neuro trans-

mitters, it must be realized that evolution of other components

of the system, such as G-proteins, adenylate cyclase, phospho-

lipase C, calmodulin, calpain, and the neuropeptides them-

selves, must have been going on simultaneously. Perhaps the

first receptor had a very broad specificity for any phenethyl-

amine-type compound, and this led to different receptors whenindividual processes had to be differentiated in multicellular

organisms. The earliest receptors may have been directly linked

to ion channels, as nicotinic acetylcholine receptors are

today. 133 Still later, coupling of receptors to adenylate cyclase

or to phospholipase C may have resulted in further differenti-

ation into receptor sub-types such as the a,, a2,/I1, and P2adrenergic receptors.

An example of the ancestral connection between apparently

disparate receptors is the recent discovery of the homology that

exists between the P-adrenergic receptors, the muscarinic

acetylcholine receptor, and rhodopsin (which absorbs light).134

All three types have seven transmembrane segments as well as

a number of other aspects of homology in their amino-acid

sequences. Glycine receptors and GABA receptors have been

similarly matched. 135Ancestral relationships are also apparent amongst the

receptor ligands, in particular the neuropeptides. Well-known

' amilies' of neuropeptides include the VIP-secretin group,

which also includes PHM, PHI, and GIP,13' and the CCK-

gastrin group, which have in common a C-terminal pentapep-

tide.136This pentapeptide is also shared with a peptide that has

been isolated from the skin of some amphibians, namely

caerulein, which has a similar bioactivity to CCK.1370ther

peptides with potent activity in mammalian systems, such as

physalaemin, kassinin, and eledoisin (all of which are homo-

logues of substance P), bombesin, and sauvagine, have been

isolated from amphibian Extensive studies have alsobeen made of the bioactive peptides of sea-squirts and jawless

fish, and have also pointed to an evolutionary relationship

between peptides of the same family. 13' Furthermore, several

bioactive peptides are found in organisms as primitive as the

unicellular Tetrahymena pyriformis. 138 This strongly supports

the idea that organisms used these substances for general

cellular communication and later adapted them for the more

specialized role of neurotransmitters and , still later, as endocrine

hormones.13 Endocrine glands as we know them only first

appear in vertebrates, whilst primitive nervous tissue is found

in the simplest multicellular animals, including sponges. 3

In many cases, the functions of particular bioactive peptides

as neurotransmitters are unrelated to their functions as

endocrine hormones. For example, TRH is found as a

neurotransmitter in many lower species that lack TSH or athyroid gland, and appears to have been co-opted as a releasing

factor for the secretion of TSH in higher c a ~ d a t e s . , ~ ~t should

be noted that no classical or peptidyl neurotransmitter has any

intrinsic vascular, gastro-intestinal, or neuronal activity, but

that its effects are dependent on the range of functions carried

out by its secondary messengers in a particular tissue.

As well as a phylogenetic relationship existing between

various neurotransmitters, it has been suggested that an

ontogenetic relationship also exists. The best-known example

is that postulated by Pearse, the so-called APUD (Amine

Precursor Uptake and Decarboxylation) theory, which states

that neural and endocrine cells that show particular character-

istics have a common embryonic origin.140This theory is not

universally accepted,141 u t it does emphasize the unified nature

of the neuroendocrine system,These relationships between neurotransmitters directly affect

drug design. The common model should enable drugs to be

designed that are specific for their own particular receptors, but

with structural features in common.

3 Discovery of CNS Drugs

The discovery of drugs is based on two approaches :knowledge

of the biochemistry of the disease to be targeted and the

preparation of compounds that have a structural analogy with

known active types.

In most cases, knowledge of the biochemistry of diseases has

been retrospective to the discovery of active drugs, particularly

those that are CNS-active. The reason for this lies in the

difficulty in understanding brain processes and in isolatingreceptor prote ins; so far, detailed knowledge is only available

on the nicotinic acetylcholine 143 but recent results

suggest that such knowledge will soon be available for GABA

receptor^,'^^ glycine and noradrenaline P-recep-

Much more information is available on enzymes and

related diseases and this has led to several successful drugs, the

most notable in the CNS area being the inhibitors of the

monoamine oxidases (MAO).14'

The use of antipsychotics in the treatment of schizophrenia

is a clear illustration of how biochemical processes have been

clarified as a result of the use of CNS-active drugs. Although

reserpine had been shown to control psychotic behaviour,14'

only with the discovery of the antipsychotic properties of

ch l~rpromazine l~~nd the subsequent correlation between

clinical dose and IC,, values of the more potent antipsycho-was it possible to develop the antidopaminergic hypo-

thesis for the action of these drugs. The fact that other

neurotransmitter systems are also invo1ved12' suggests that still



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NATURAL PRODUCT REPORTS, 1988-R. I. BRINKWORTH, E. J. LLOYD AND P. R. ANDREWS 377

M eI

M P P P

deprenyl

0

MPTP

Figure 11 Formation of the active metabolite, MPP', of MPTP.

more complex biochemistry remains to be elucidated, possibly

by use of other CNS-active drugs.

Greater success has been obtained from optimizing the

structures of compounds that have a known activity. Histori-

cally, these so-called lead compounds have been derived inways that are described in the following sections.

3.1 Ethnopharmacology

Undoubtedly, the first drug discoveries resulted through the

interaction of primitive peoples with their environment. 150 The

majority of plant products were found to be suitable for food,

but others would have been poisonous, psychotropic, or

medicinally useful. CNS-active plant extracts became associated

with social and religious rites as a result of their ability to

induce euphoria or otherwise alter the conscious state of the

user.

Discoveries of drug (as against nutritional) effects of plants

were made in the context of a tolerant, leisurely way of life

where serendipity, rather than a rational scientific approach byactive investigation, played a major role. Because these cultures

developed slowly, the use of psychoactive plants and their

extracts became, and in many cases remains, an accepted part

of the life of ancient peoples. Examples include the use of khat

(Ethiopia), fly agaric (Siberia), opium (S.E. Asia), cannabis

(Middle East), and cocaine (South America).l5l Thus the use of

drugs, whether natural or synthetic, for recreational purposes

is not a recent aberration: rather, the scale and impact on

societies has been amplified.

Indeed, we might identify a new 'ethnopharmacology' as a

sub-cultural aspect of modern societies, but with a change in

emphasis to active attempts to circumvent modern, prohibitive

laws. There have thus arisen, in conjunction with the

development of scientific knowledge, sophisticated approaches

to drug manufacture, in the form of clandestine laboratories.1.52Although, in most cases, this trend has increased the problems

of controlling drug trafficking and addiction, there has recently

occurred a case where a toxic by-product that was obtained in

such a laboratory may, curiously, in the long run prove

benefi~ia1.l~~hus the presence of MPTP as a by-product of the

synthesis of MPPP (Figure 11) led to the poisoning and death

of heroin addicts, with the victims showing the classic symptoms

of Parkinson's disease. 54, 155 Subsequent investigations showed

that the symptoms were probably due to the toxic metabolite

MPP+.154 ince monoamine oxidase B (MA0 B) acts on MPTP

to produce MPP+,156*157ts effects may be nullified by using

M A0 inhibitors such as deprenyl. An outcome of this episode

is that trials have been instituted into the use of deprenyl (aM A0 inhibitor) and tocopherol in the control of the symptoms

of Parkinson's disease.lssSo, ironically, the persistent tendency of people to explore

the recreational uses of drugs has produced support for the

hypothesis that Parkinson's disease is the result of a toxic

Me

1,

8MPPf

substance (but not necessarily MPP') in the en~ iro nme nt .' ~~n

addition, it is now possible to define a reasonable animal model

for what had previously been seen as an anthropocentric

disease. 6*

3.2 Medicinal Plants

Medicinal plants have been the source of therapeutic substances

for centuries,15*but single substances ( e .g . morphine, salicylic

acid, and quinine) were not isolated until the nineteenth

century. With the development of synthetic and analytical

techniques, chemists modified the structures of active substances

in an attempt to improve potency and lessen side-effects.

The classic example of this approach is morphine, which has

undergone considerable investigation. Thus the five fused rings

have been systematically pruned,161 leading to sub-structures

which retain similar analgesic properties to morphine (Figure

12); in addition, the effects of various substituents have been

extensively investigated162 Figure 13). The increased potencyof these sub-structures supports the hypothesis of an analgesic

pharmacophore, consisting primarily of a phenyl ring and a

nitrogen atom, with substi uen s providing differential activity

at the various sub-types of opioid receptor. Numerous models

for opioid analgesic activity that contain this pharmacophore

have been However, increasing the complexity of

the morphine nucleus has also led to structures of increased

potency. For example, etorphine (Immobilon) has 8600-times

the potency of morphine162 Figure 13).

The discovery and structural determination of the endo-

genous opioid peptides methionine-enkephalin (met-enkepha-

lin) and leucine-enkephalin (le~ -enkephal in*)'~~,64 prompted a

quest for the structural correspondence between morphine and

the enkephalins. This problem is still not entirely solved,

deduction of the active conformation being difficult due to theflexibility of these peptides. So far, alternative conformations

of opioid tetrapeptides superimposed on morphine and etor-

phine, and of leu- and met-enkephalin on PET, have been pro-

p 0 ~ e d . l ~ ~

The morphine example, and those of other plant products

that have been successfully investigated to produce improved

justifies continuing the search for active principles of

plant products but in a systematic way, despite the low success

rate. One reason is illustrated by the structure of morphine,

which, being an over-determined rigid analogue of the

enkephalins, could not have been logically deduced from the

enkephalins, given their prior discovery. In turn, potent

molecules such as etorphine would probably not have been

discovered. There is also a rational basis for screening natural

* To avoid confusion between the N-terminally extended compounds and the

parent enkephalins, these are often identified as [Met5]enkephalin and [Leu5]-

enkephalin : see 3AA-22.2 of IUPAC-IUB Recommendations (1983) for

Nomenclature and Symbolism for Amino Acids and Peptides.



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378

Me

NATURAL PRODUCT REPORTS, 1988

Me\

I

Me

\ethadone (10)

Me /

HqNlevorphanol (I)

‘Me

pethidine (lo3)

tMe\

OH

morphine (2.5)

M e\

Me

\

HO Me

M e

metazocine (15)

HO

OMe OH

K ’- met -enkephalin (4 )

etorphine, R =Me (0.15)

PET R=CH2+

Figure 12 The effect of structural changes on morphine activity. The figuresin parentheses are consensus Ki values (nmol dm-3),based on a largenumber of literature values. The dotted arrow shows the conformational similarity between met-enkephalin and PET.

products: most have similar precursors (e.g.amino acids) to

those of animalslG6 nd, as a consequence, are inherently likelyto interact with the biopolymers of receptors (e.g. roteins) in

an analogous way.

3.3 Toxic Substances

As emphasized by Albert,lG7oxicity is a relative concept, the

emphasis in drug discovery being on the search for selective

toxicity. The investigation of toxic properties of synthetic

molecules has been referred to in Section 3.1 in relation to the

narcotic MPPP. Amongst natural products, atropine, mus-

cimol, tubocurarine, and ergotamine are well-known examples

whose toxicity initiated enquiry that culminated in discovery of

useful drugs.168Only the ergot alkaloids, which have recently

been reviewed,165will be discussed here.

The fungus Cluviceps purp ureu, which is a parasite on ryeplants, is the source of four main classes of ergot alkaloids169

(clavines, lysergic acids, lysergic acid amides, and ergot peptide

alkaloids) whose collective toxicity, first described several

centuries ago, includes vomiting, diar rhoea, thirst, convulsions,

tachycardia, confusion, coma, and hallucinations. 165 Moderninvestigations have shown that the major class, the ergot

peptide alkaloids, consists of five structural types and their

isomers : ergotamine, ergosine, ergocristine, ergocryptine, and

ergocornine (Figure 14). The multitude of symptoms of ergot

toxicity prompted a search for structure-activity correlations

that would specify particular effects devoid of toxicity. This has

led to several useful

Many ergot-derived structures have had to be rejected either

through severe toxic properties or because of their chemical

lability in vivo. The search for new derivatives of ergot alkaloids

continues with the setting up of host-free culture systems for

the fungus and the isolation of novel metabolites, together with

further chemical manipulation of the various ergot structures. 165

The latter process is based on the recognition of three

interrelated clinical, biochemical, and structural facts : the widevariety of biological action of the ergot alkaloids (see Table 6);the multiplicity of their binding activity, as shown by the IC,,

values of eight different ergot alkaloids and their derivatives in

(see Table 6 and Figure 15).



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NATURAL PRODUCT REPORTS, 1988-R. I. BRINKWORTH, E. J . L L O Y D A N D P. R . A N D R E WS 379

/ther substitution reduces

potency and/or increases

toxicity

3 -OMe, 7xc

3 -OAc,!

f

N - v P h , 6 x1

N -V/\ ,antagonist

8

Me,\ -17

i n 16/7 "

/

OH

morphine I

5 -Me,

6-OMe, 10x4

6-H, 10x4

6 -N3, 50x4

Figure 13 The effect of substituents on morphine activity.

? X C O N H -

HNJ

reduced 6, 14 bridge, 3 - OMe, 1OOxf

fdiprenorphin

1 4 - 0 H , lox!

14 -OAc, 200x414 - -Me, SOOOf

6 - N3/14

/*'--\

/ -.(+Me

OHOMe

substituents

give large etorphine

increases 8600x f70 - W P h , 700x

-HR1

H

Me CH2Ph ergotamine di hy droergotamine

Me i -Bu ergos ine

i-Pr CH2Ph ergocristine dihydroergocristine 33%

i-Pr i-Bu

i-Pr i-Pr ergocor nine dihydroergocornine 33%

ergocrypthe dihydroergocrypt ine a :p, 22:11% ergoloid-mesylate

Figure 14 Structural types of ergot alkaloids.



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38 0 NATURAL PRODUCT REPORTS, 1988

Table 6 Biological activity of ergot-derived

Drug Activity

Ergotamine Antimigraine

Dih ydroergotamine Antimigraine, vascular headache,

Me h ylergome rine

Methysergide Carcinoid syndrome, antimigraineMethergoline Antimigraine, vascular headache

Dihydroergocristine Antihypertensive, venotonic

orthostatic disorders

Obstetric, post-partum haemorrhage

Dih ydroergocornine

Dih ydro-a-ergocryptine

Dihydro-/3-ergocryptine

Nicergoline

Lysergol

LSD

Bromocriptine

Lisuride

Pergolide

LY 141-865

Ergoloid-mesylate : antihypertensive,

treatment of cerebral insufficiency

a-1Adrenoceptor blocker

An ti hypertensive

Hallucinogenic, anxiolytic,

antidepressant

Antiprolactin (galactorrhoea),

antidepressant, anti-Parkinson's

Antiprolactin

Dopaminergic, anti-Parkinson's

Antihypertensive

R

methylergometrine, R =H

methysergide , R=Me

Ii- Bu

br om ocrip t ile

eight receptor-binding assays12' [see profiles (e) and (f) inFigure 101; and the fact that the structures of three of theneurotransmitters whose receptors are affected (dopamine,noradrenaline, and serotonin) may be considered to existwithin the lysergic acid p 0 rt i0 n . l ~ ~t is also possible to matchth e CC K tetrapeptide analogue Trp-Gly-Gly-Phe topog raphi-cally onto ergotamine in a low-energy conformation, thusestablishing a possible structure-activity relationship betweenCC K and ergotamine. 131 So far, struct ural investigations haveconcentrated on either the intact alkaloids or the truncatedlysergic acid moiety. Modification of the tricyclic non-LSDfragment (Figure 14), for which an improved synthesis hasr e c e n t ly be e n p~ b l i she d , ~ '~ould also be fruitful.

3.4 Analogues of Endogenous Molecules

The discovery tha t drugs act on neurotransmitter systemsinitiated the idea that all or part of the structure of aneurotransmitter matches a portion of the drug. However,most drugs and neurotransmitters have a large number of

alternative low-energy conformations in which they may bindat their receptors. This has led to the use of the rigid-analoguetechnique, in which a drug structure or its analogue is fixed in

M e N l

methergoline

M6 nicergoline

&,--HN

@

HN

ly sergol

B

LSD lisuride

Figure 15 Useful drugs based on ergot alkaloids.

pergolide LY 141 -865



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NATUR AL PRODUCT REPORTS, 1988-R. I . BRINKWORTH, E. J . L L O Y D A N D P. R . A N D R E WS 38 I

HN O o H

Muscimol(O.024) Imidazole-4 -ace tic acid (0.2 4) Isoguvacine (1 .4 )

L N M e 2 C l - H2N- COOH

0

THIP ( 2 . 6 )

(+)- Bicuculline methochloride (7 ) G A B A (0.34) Baclofen (--)

HN6 6 HN s" H60-Proline (14) Isonipecotic acid (15 ) Nipecotic acid (>100) Homo nipeco tic acid (>100)

Figure 16 Rigid analogues of GABA. Figures in parentheses are IC,, values (pmol dm-3), taken from ref. 172.

a given conformation by incorporating a minimum number of

necessary connecting atoms without substantially affecting

physicochemical properties. For example, the dopamine agonist

2-dipropylamino-6,7-dihydroxytetralinADTN)17' was devel-

oped as a rigid analogue of dopamine. Similarly, comprehensive

efforts have been made to define the active conformations ofGABA, either by limiting its abundant flexibility (by using

rings, double-bonds, or restricting groups172)or by studying

natural products and their synthetic analogues (muscimol,

ibotenic acid, and bicuculline) in which these devices are

already incorp~ratedl~~Figure 16). This has resulted in the

clinically useful compounds THIP and b a ~ l o f e n , ~ ~ ~s well as

numerous experimental compounds that have advanced our

understanding of the pharmacology of GABA.I6' For example,

it is now likely that three sub-types (A, B, and C) of GABA

receptor exist.174

Similar attempts have been made to define the active

conformations of endogenous peptides, and this process has

already been illustrated for the enkephalins (Section 3.2) and

CCK (Section 3.3). In those cases, a given natural product

(morphine and ergotamine, respectively) was assumed to be arigid analogue of all or part of the peptide molecule. The

reverse process, in which the endogenous peptide is restricted

without knowledge of a natural or synthetic product acting at

the same receptor, has also been carried out. The methods for

introducing conformational restrictions into peptide structures

include : (i) introduction of cross-linking groups, generally

disulphides ; (ii) replacement of individual L-amino acids by

corresponding D-forms; (iii) introduction of restrictive ana-

logues of the peptide bond ( e . g . ethylene, cyclopropane, or

retro-amide groups); (iv) replacement of flexible bonds in the

peptide backbone with rigid structures ( e . g . by using proline

rather than existing amino acids) to limit rotation around the

C(ol)-N bond.

The preceding techniques can be illustrated by the develop-

ment of somatostatin analogue^.'^'-^^^ Somatostatin is a peptidehormone, named from its ability to inhibit the release of growth

hormone, but it also inhibits the release of insulin, gastrin, and

other hormones, as well as lowering glucogen 1 e ~ e l s . l ~ ~he

properties suggest several therapeutic possibilities but these are

limited by two major problems: the peptide is very short-

acting, due to its rapid metabolism, and is not active orally:

somatostatin has a relatively non-specific activity, since it

inhibits the release of many different hormones simultaneously.

Somatostatin consists of fourteen amino-acid residues. It hasbeen shown, by a combination of n.m.r., computer-graphic,

and structure-activity techniques (using the methods listed

above), that this number could be contracted to just five plus a

single proline residue to replace the other nine.17' The successive

stages of modification are illustrated in Figure 17. The resultant

Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys

1, Somatostatin

cyclo-(Aha-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Ser)

I

2

I

cyclo-(Aha-Lys-C~s-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-Ser)

3

cy c lo -(A ha - Phe Ph e-D-Trp-L s-T r-P he )

4

4

I

c ydo-( Aha-Cis-Phe-D-Trp-Lys-Thr-C$s)

5

c y clo - Pro P he D -Trp-L s-T r Ala)

6

cyclo-(Pro-Phe-D-Trp-Lys-Thr-Phe)

7

I

4

Figure 17 Structural modifications of somatostatin



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cyclic hexapeptide 7,which retains only residues 8 to 10(8 now

being a D-tryptophan residue) has a comparatively restricted

conformation and is not amenable to metabolism by trypsin,

with the result that its activity is significantly longer-lasting

than that of somatostatin. Thus 7 continues to show activity

after more than five hours, while somatostatin has ceased to

display action within one hour. The activity of 7 relative to

somatostatin is excellent : inhibition of the release of growth

hormone is1.74

times greater in vitro and approximately20times greater in vivo, and inhibition of insulin release is

approximately five times more powerful. 17 ' The compound also

displays oral activity. It is presently in clinical trial for the

treatment of diabetes and may have potential in other disorders.

3.5 Synthetic Compounds

Some of the earliest drug discoveries resulted from screening of

synthetic compounds, using random procedures, with promis-

ing candidates being submitted for more extensive examination.

Cl~nidine,"~hl~rpromazine, '~~nd diazepam179 re examples

of drugs whose CNS properties were discovered by chance.

Whereas twenty to thirty years ago one in 2000 newly

synthesized chemicals was successfully marketed,165 the ratetoday is more difficult to estimate, but is probably considerably

less.

Nevertheless, medicinal chemists have continued to synthe-

size novel structures by exploiting the combinatorial richness of

carbon compounds to form rings, chains, and multiple bonds

that lead to chirality in various forms and to include

heteroatoms in order to modify electronic and steric effects.

The underlying process of discovery has consisted of making

minimal structural changes to lead compounds in response to

feedback information from testing these compounds in bio-

logical systems. However, it is possible that the vast amount of

information embodied in the resultant hundreds of thousands

of structures could be used, as follows, to design CNS drugs

more rationally.

The previously defined common structural model (Section2.9), based on representative CNS-active drugs, not only

defines the minimum structural requirements for CNS activity

in general but also allows us to define the specific spatial

relationships between the secondary binding groups that are

important for a particular activity and the primary groups,

phenyl and nitrogen, of the common model. The co-ordinates

for these primary groups, as well as the secondary binding

groups for various classes, have been determined.180*181 Thus

the common model leads us to the placement of these primary

and secondary binding groups without stipulating the connect-

ing framework, which is left as a 'wild card' to be achieved by

any construction which preserves the prescribed locations.

Therefore, a procedure for the development of structures

that are potentially capable of CNS activity, based on the

common model, would consist of three phases :(1) locate the primary groups phenyl and nitrogen on some

suitable framework in the topography defined by the

common model ;

(2) place the secondary binding groups that are necessary for a

specified activity in the correct position on the framework.

Clearly, this step requires some forward thinking in phase

1 to make sure that appropriate atoms are available to

which secondary groups can be attached;

(3) judiciously remove any unwanted atoms in such a way that

the locations of key groups are preserved.

Because this approach is topographical, carrying out these

operations requires viewing the developing structures in three

dimensions by using computer graphics (see Section 3.6).A related approach has been suggested by Warrener et al.,lSz

whose method, termed MOLRACla3 nvisages the use of rigidalicyclic systems of known shape and size to space functional

groups at exactly designated positions. This concept is not new,

having been exploited in the design of neuromuscular blocking

agents,la4 transition-state a n a lo g ~ e s , '~ ~nd opioid an-

a l g e s i c ~ . ' ~ ~ ~ ' ~ ~owever, in some cases it has suffered from the

limitation of being predominantly a two-dimensional tessela-

tion process or else topological in approach.

Suitable frameworks and building blocks for this procedure

include the many structures that are known to have CNS

activity, as well as synthetic organic compounds and natural

products. Ideally there should be a high degree of rigidity, or

else limited flexibility, in the initial structures to ensure thatminimal alteration to the locations of binding groups can

occur. Amongst rigid molecules already demonstrated as fitting

the common model, morphine, LSD, strychnine, mianserin,

diazepam, apomorphine, clonidine, bicuculline, and the ergot

alkaloids provide excellent starting points. The polycyclic

structure of strychnine suggests the use of cage compoundslaS

such as adamantanelas as frameworks on which to graft the

necessary groups.

3.6 Drug Design

The term 'drug design' has a different meaning for different

researchers, depending on their area of research. This was

emphasized at a recent conference, lgowhere drug design wasacknowledged to be the rational use of a collection of different

methodologies leading to the discovery of a new drug. These

methodologies were agreed to have two purposes: lead

generation and lead optimization, lead generation being

achieved by first identifying the relevant biochemical pathways

and then synthesizing the appropr iate agonists and antagonists.

However, there was no general acceptance of any one technique

for lead optimization, although QSAR methods1g1 i.e.methods

based on quantitative structure-activity relationships) rated

best.

Whereas the QSAR methods handle data from the level of

organisms down to individual cells and receptor preparations,

more recent techniques, which may be classed as three-dimensional QSAR, have been developed which attempt to

define the struc tural arrangement that is adopted by moleculeswhen they bind to a receptor (the recognition process).

Approaches to the design of drugs from this viewpoint

depend on one or more of three requirements :

(1) knowledge of the structure of the biological macromolecule

involved. For example, X-ray structures for various

enzymes (e.g. dihydrofolate reducta~e~~~)nd hormones

( e .g . insulin193) rovide clues to the structural requirements

of the molecules that bind to them;

(2) knowledge of the mechanism involved. For example, the

involvement of coenzymes and their implied location at the

enzyme-substrate reaction interface (as determined from

molecular-orbital calculations) allows the transition-state

geometry of the substrate to be approximated, thus

providing a basis for the design of transition-state an-

alogues ;la5(3) knowledge of the structures and properties of the drugs

involved. CNS drugs fall into this category; whereas

comparatively little is known about the three-dimensional

structure of CNS receptor-binding sites, there is an

abundance of information about the structures of an

enormous range of different CNS-active

Having postulated a pharmacophore, the strategy is to

discover from the structures of drugs of known activity the

common three-dimensional relationship between key atoms in

groups of different molecules. However, since many CNS-

active drugs show a diversity of structure as well as several

degrees of conformational freedom, resulting, in some cases, in

there being many millions of conformers to be considered,lg6

the problem then becomes one of reducing the number of

possibilities. The most likely conformers are usually determined(on an energetic basis) from X-ray crystallography, lS7from

nuclear magnetic resonance (n.m.r.) spectroscopy, g8and from

potential-energy calculations. S9 Being derived from the solid

l g 5



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NAT URA L PRODU CT REPORTS, 1988-R. I. BRINKWORTH, E. J. LLOYD A N D P. R. ANDREWS 383

(X-ray), solution (n.m.r.), or isolated states (molecular-orbital

and molecular-mechanics), the resultant conformers represent

a highly informed guess at those adopted in what has been

called the fourth, or biological, state.200Further reduction in

the number of possibilities is achieved by using techniques such

as distance geometry201and the active-analogue approach,lg6

whereby optimal molecular geometries are correlated with

biological potency.

The role of computers in drug design has been emphasized inrecent books and reviews which show their use in organizing

and discerning patterns from data, as well as in performing

large-scale calculations or for completely searching the con-

formational space of a molecule.187,202-208 Other applications

include mathematical modelling,209 omputer-graphic analysis

of macromolecule-substrate interactions,210 and searching

da taba~es .~ l ' -~ l~he major techniques of computer-assisteddrug design have been ranked by Hopfinger204n a hierarchy of

their applications.

Many software packages are a ~ a i l a b l e ~ ~ ~ * ~ ' ~ .a7 for drug

design, and most contain programs for

(1) data acquisition and model building;

(2) calculation of molecular properties and conformational

(3 ) display and manipulation of structures in an interactive

(4) plotting in two and in three dimensions.

energies;

computer-graphic mode ; and

4 Conclusion

Drug discovery has been based on the investigation of structural

and mechanistic analogies between natural and synthetic

molecules and endogenous counterparts in the CNS (Figure

18). This approach rests on the large body of knowledge

showing that biochemical pathways and organic reactions use

the same bonding interactions and mechanistic processes.

Examples include the many enzyme-based reactions215 hydro-lysis, condensation, transamination), coenzyme reactions216e .g .catalysis of carbanion reactions by thiamin diphosphate),

rearrangement^'^^ (the Claisen rearrangement of chorismate to

prephenate), (pheno1,c coupling), and cyclizations2ls

(the Pic et-Spengler reaction).

Medicinal chemists and biochemists find the use of structural

and mechanistic analogies attractive, mainly because they are

consistent with life processes being a continuum of universal

chemical processes. Thus, concomitant with biological evolu-

tion of shape and function, there has been evolution of

chemical Evidence to support this includes the well-

established fact of the evolution of proteinsZ2O e .g . proteolytic

enzymes), with its implication that receptor proteins probably

evolved into sub-types to provide subtle ways of attenuating

electrical signals 221 the evolution of neurotransmitter func-tions, as shown by the wide phylogenetic distribution of

neurotransmitters222 and by the recent demonstration that

Figure 18 Structural and mechanistic analogies between natural and synthetic molecules. The shaded area em phasizes the comm on biosyntheticlink between organisms.



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biochemical agents of vertebrate endocrine and nervo us systemsprobably orginated in unicellular organisms ;219 and the widelyaccepted scenario for the evolution of living cells from non-living materials, i.e. chemical

Tw o other findings supp ort the pursuit of dru g design basedon the use of structural and mechanistic analogies. First,there is the discovery that low-energy conformations ofrepresentatives of different classes of CNS drugs, together with

their rigid analogues a nd neurotran smitter molecules, share acommon topographic arrangement of drug-receptor bindinggroups (i.e. a common pharmacophore, Section 2.9). Thiscommon structural component, which has been extensivelyverified for 67 CN S drugs,lso*lel rovides a ‘skeleton key’ towhich all CNS drugs may conform in binding t o their receptors.

Secondly, it has long been recognized that chem ical reactions,whether biochemical or synthetic, proceed alo ng pathways withminimum breaking and making of bonds (i.e. with a redistri-bution of a minimum number of valence electrons). Thismechanistic concept has recently been quantified into a prin-~ i p l e ~ ~ ~the principle of minimum chemical distance’(PM CD )-an d the resultant a lgorithm h as been used todemo nstrate and successfully to predict both biochemical (e.g.the isoprene rule) and syn thetic (e.g. he synthesis of strychnine)

pathways.224 he key roles that are played by a-amino acidssuch as glutamic acid and tyrosine (Figure 18), whether asbuilding-blocks in proteins, at active sites of enzymes andreceptors, or biotransformed into neurotransmitters, becomeobvious.

Thu s there is a comm on structu ral basis on which drugs andneurotrans mitters act at C N S receptors which may be furthe rrelated to a common mechanistic principle by which neuro-transmitters and receptors have synergistically evolved alongwell-established biochemical pathways. The mechanistic prin-ciple provides a nexus between our understanding of brainbiochemistry and the frequent use by medicinal chemists ofstructural analogies (Figure 18). Knowledge of these underlyinggro und rules, together with the potential to engineer geneticallyand to express receptor protein sequences, will provide greater

predictability in the design of novel drugs.

Acknowledgements

The authors acknowledge the assistance of Jackie King intyping this manuscript and of Jos Smith and Rae McPhee inpreparing the artwork.

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