Pharmaceutical Sciences 3320

8/6/2019 Pharmaceutical Sciences 3320

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Pharmaceutical Sciences 3320 - Principles of Drug Action

Functional Groups, Acid Base Chemistry and

Physicochemical Properties

Lecture Material

Introduction

Drugs are organic compounds, and as a result, their activity, their solubility in plasma

and their distribution to various tissues is dependent on their physicochemical

properties. Even the interaction of a drug with a receptor or an enzyme is dependent

on characteristics of a drug molecule, such as ionization, electron distribution, polarityand electronegativity. If we are to understand drug action, we must also understandthe physicochemical parameters that make this action possible. The following sections

are intended to explain the acid-base and physicochemical properties which determine

drug action.

Functional Group Review

Simple Hydrocarbons

As shown below, there are three electronic configurations of carbon which are regularcomponents of drug molecules. Carbon has an atomic number of 6, and a molecular

weight of 12.01, and has 4 electrons in its valence shell. It can exist in three distinct

geometric forms based on three distinct hybrid orbitals. The carbon speciesdesignated sp3 is tetrahedral in shape, with bond angles of 109.5 degrees.

Hydrocarbons containing sp3 carbons are known as alkanes. In this form of

carbon, chirality is possible, as will be discussed below. The carbon designated sp2 isplanar and trigonal in shape, due to the presence of a pi orbital containing one

electron. These hybrid carbons are present in the double bond, and the compounds

containing this group are known as alkenes. The bond angles in this form of carbon

are 120 degrees.


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Carbon can also exist in a linear form known as an sp hybrid, and compoundscontaining these carbons are known as alkynes. The bond angles in alkynes (also

known as acetylenes) are 180 degrees, and they have two sets of pi orbitals, eachcontaining on pi electron.

Like carbon, many heteroatoms possess specific geometries which contribute to the

overall shape of drug molecules. Nitrogen, an abundant heteroatom in drug molecules,

has an atomic number of 7 and a molecular weight of 14.008, and has 5 electrons in

its valence shell. It generally exists in a tetrahedral shape that is similar to carbon,except that one of the 4 bonds is to a lone pair of electrons. As we shall see later, this

lone pair is crucial in determining the acid-base properties of drug molecules at

physiological pH. Unlike carbon, the tetrahedral form of nitrogen is not chiral, since at

ambient temperature it undergoes a rapid inversion known as Walden inversion,wherin the lone pair shifts from one side of the atom to the other and back again. As

will be discussed later, nitrogen can also exist in a trigonal form which is analogous to

an sp2 hybridized carbon.

Oxygen, which has an atomic number of 8 and a molecular weight of 16.00, has 6

electrons in the valence shell, and is most often found in the form shown below. In

this form, oxygen has 2 pairs of pi electrons, and a bond angle of 104.5 degrees. As

you are aware, oxygen can also exist in a doubly-bonded form, such as is found in a

carbonyl group. There are still two pairs of pi electrons, but the geometry of this type

of oxygen is obviously quite different.


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Phosphorus has an atomic number of 15, and a molecular weight of 30.97, with 5electrons in the valence shell. In drug molecules, it exists in two major forms, the

trivalent form (with one lone pair of electrons) and a pentavalent form (no lone pairs).

In drug molecules, there are also two prevelant forms of sulfur, which has 6 electrons

in its valence shell. One is a linear form with two lone pairs of electron, as shown

above, and the other is a hexavalent form with no lone pairs.

The hydrocarbons known as alkanes have no electronegative groups, and cannot form

hydrogen bonds. This is due to the absence of a dipole moment, in which electronsare pulled towards an electronegative atom. As such, alkanes are very insoluble in

water, since formation of H-bonds with water is a prerequisite to water solubility.

Alkanes are also chemically unreactive. When 4 different groups ar bound to a singlecarbon, the possibility ofisomers arises. As shown below, compounds with a

single chiral center can exist as enantiomers, which are isomeric forms that are

mirror images.


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Alkenes are carbon compounds that contain sp2-hybridized carbons, as seen below.

These analogues still have no electronegative groups, and since there is no dipolemoment, they are unable to H-bond. This imparts low water solubility to this series.

Alkenes are hydrophobic, and somewhat chemically unreactive. In addition, alkenes

exhibit geometric isomerism, and can exist in cis and trans forms. The cis form is

known as the Z-isomer. derived from zusammen (the German word for together), andthe trans form is termed the E-isomer, from the word entgegen (the German word for

opposite).

The third common form of carbon found in drug compounds, the alkyne, contains sp-hybridized carbon, as shown above. There is a strong dipole in these compounds, such

that the terminal hydrogens are acidic in strongly basic conditions. At physiological

pH, these compounds are hydrophobic, and exhibit poor water solubility.


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A subset of the alkenes are the aromatic hydrocarbons. Aromatic hydrocarbons

contain conjugate double bonds, and when these double bonds conform to the Huckle

Rule (i.e. they have 4n + 2 pi electrons), the resulting hydrocarbon is aromatic.

Hydrocarbons that contain halogens, such as butyl bromide (below) have a strong

permanent dipole, due to the electronegativity of the halogen. However, they are stillunable to hydrogen bond, and as such have poor water solubility.

A key point to remember is that the solubility of an organic compound in water isdictated by two factors: whether it can form hydrogen bonds with water, and/or

whether it dissociates to form an ion. Compounds that lack these two traits will be

generally water insoluble.

Hydrocarbons Bonded to Heteroatoms

Heteroatoms such as oxygen, nitrogen and sulfur give drug molecules the ability to

form hydrogen bonds, and thus impart some degree of water solubility. However, the

overall solubility of a given molecule also depends on the hydrophobicity of the alkylgroup (i.e. octyl alcohol would be less soluble than ethyl alcohol).

As shown in the figure below, alcohols can exist as primary, secondary or tertiaryalcohols, depending on the number of groups appended to the carbon attached to the

oxygen. Alcohols also possess a permanent dipole moment, and as such they can H-bond to themselves, and to water. In addition, alcohols can undergo biological

oxidation, an important feature in the metabolism and excretion of many drugs. A

primary alcohol such as ethanol can be oxidized in vivo to an aldehyde(acetaldehyde), and then to the corresponding carboxylic acid (acetic acid). Secondary

alcohols are oxidized to the corresponding ketone (e.g. isopropanol is converted to

acetone), and tertiary alcohols are stable to oxidation, since they do not possess the

alpha hydrogen needed to participate in the reaction.


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When a hydroxyl group is appended to an aromatic ring, the resulting alcohol isknown as a phenol. The simplest example is the phenol derived from benzene, which

is known as "phenol". Phenols are weak acids, because they can dissociate in water to

form the corresponding phenolate anion. This dissociation is more facile due toresonance stabilization of the phenolate, in which the negative charge delocalizes into

the aromatic system. Phenol acidity is strongly affected by other substituents on thearomatic ring. As shown below, p-nitrophenol is more acidic than phenol, due tothe electron withdrawing group (EWG) (nitro), while p-ethylphenol is less acidic,

owing to the ethyl electron releasing group (ERG). It should also be pointed out that

phenols, when treated with aqueous base, can form the corresponding salt form, and

these entities can be isolated, This becomes important when a phenolic drug needs to

be dissolved in an aqueous environment.


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An ether is an oxygen containing functional group wherein the oxygen is flanked by 2alkyl groups. Although these compounds can H-bond weakly to water, they are not

sufficiently polar to be water soluble. They are also chemically inert unless exposed to

a spark or flame. On the left in the figure below is the general structure of an ether,

showing the two lone pairs of electrons on the oxygen, where R1 and R2 are both

alkyl or aryl. The structure on the right is, of course, the ether bunny!


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Aldehydes and ketones contain a carbonyl group, which is responsible for the

properties of these molecules. As shown below, the electronegative oxygen pullselectrons, and sets up a dipole moment. This confers a partial positive charge on the

sp2 carbonyl carbon, and a partial negative charge on the oxygen. As shown,

aldehydes and ketones can H-bond to water, conferring some degree of water

solubility. They also undergo a keto-enol tautomerism, as shown in the diagram.

Because the carbonyl carbon has a partial positive charge, it becomes susceptible tonucleophilic attack. This is easily accomplished, since the carbonyl has thye ability to

accomodate the negative charge. In such a reaction, the carbonyl carbon is converted

from sp2 to sp3, and then back again to sp2 following the departure of a leaving

group. This process is known as nucleophilic substitution.

One of the most prevalent acid-base functional groups in drug molecules is the amine

group. As seen below, these nitrogen-containing compounds can exist as primary,

secondary, tertiary and quaternary amines, depending on how many alkyl groups areappended to the nitrogen. Note that in the primary, secondary and tertiary amine

molecules, a lone pair of electrons is present, and as such these compounds are weak

bases. When the lone pair is used to form a covalent bond with a fourth alkyl group,the resulting quaternary ammonium compound has a permanent positive charge. It


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has no ability to donate or accept a proton, and thus is a neutral compound. Amines

are able to H-bond in two possible orientations, as shown above, and as a result they

have considerable water solubility.

The key to determining the basicity of an amine is to determine the availability of the

lone pair of electrons. If the lone pair is more accessible, the compound is more basic,and vice versa. The lone pair also enables amines to form salts; thus if a basic amine is

treated with Hcl, the corresponding hydrochloride salt is formed.

The structure of the alkaloid drug morphine is shown below. Note that it contains anumber of the functional groups we have discussed. The tertiary amine group and the

phenolic hydroxyl are the only two of these groups that have acid-base characteristics

in vivo. Treatment of morphine with HCl results in the formation of the hydrochloride

salt, which is ionic and therefore highly water soluble. Treatment of morphine with

NaOH produces the corresponding sodium phenolate salt, which is also water soluble.


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Carboxylic acids are very water soluble, due to their ability to H-bond with water, and

with themselves, as shown below. They also dissociate very easily, because thecongugate base form is resonance stabilized. When EWG are added to the alpha

carbon, as shown, the acidity of the carboxylate is enhanced. Thus fluoromethylacetic

acid is more acidic than acetic acid itself, and trifluoroacetic acid is even more

acidic.It should be pointed out that carboxylic acids, whe treated with NaOH, afford

the corresponding sodium salts.


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Amides, like aldehydes and ketones, undergo tautomerization, ans as such, they haveconsiderable sp2 character. For this reason (since the electrons are involved in the

tautomerization rather than in proton binding), amides are neutral.


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There are a number of derivatives of the carboxyl group which occur frequently indrug molecules, as shown above. The amide group has already been been discussed.

Carbonates and carbamates, like amides, are neutral in terms of acid-base properties.

Ureas are also neutral, and lactones (cyclic esters) and lactams (cyclic amides), like

their open-chain homologues, are also neutral. Other important functional groupsinclude nitriles (neutral), sulfonic acids (acidic), sulfonamides (acidic) sulfones

(neutral) and thioethers (neutral).

Stereochemistry


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Drug molecules must generally interact with biomolecules in a very specific way to

elicit a pharmacological response. Because biomolecules are chiral, they oftendiscriminate between isomers of a given drug molecule. In some cases, all isomers of

a drug are equipotent, in some cases only one isomer is active, and it is even possible

for one isomer to act as an antagonist to the action of the first. There are a number of

ways to measure and denote chirality. Some of these are experimentally derived,while others depend on a representation of the 3-dimensional structure.

When molecules with one or more chiral centers have the same empirical formula,and they are mirror images of one another, the isomers are known as enantiomers.

Enantiomers have identical physical properties, and as such are very difficult to

separate by conventionl means such as chromatography or crystallization. There are

three major ways to express the chirality of drug molecules:

1. D and L - these letters stand for Dextro and Levo, which are abbreviations of

the Latin words for right and left. In order to use this method, the structuremust be compared to the 3 carbon sugar D- or L- glyceraldehyde. This is done

by placing the "most oxidized group" at the bottom, and comparing the Fischer

projections of the two molecules. Although this method is good for sugars, itcannot be used for large drug molecules, since in many cases it is quite

ambiguous. Your job is to forget about this method.

2. d and l - the lower case letters d and l are used to express chirality, but in thiscase the values of d and l are determined experimentally. A solution containing

the compound is placed in a polarimeter, and a beam of plane-polarized light

is passed through the solution. The light will rotate eitherright(dextrorotatory or +) or left (levorotatory or -). Enantiomers that are pure

produce equal and opposite rotation (i.e. if the d form is +25 degrees, the l

form will be -25 degrees). A racemic mixture (a 50:50 mixture of enantiomers)has a net rotation of zero. The active form of the

neurotransmitterepinephrine is (-) or levorotatory.

3. R and S - these letters refer to the Latin words rectus (right) and sinister(left). Unlike d and l, R and S can be determined by examination of the

structure. R and S are assigned for a given chiral center by placing the lowest

priority group in the back, and then applying the following 3 priority rules:

Rule 1: The higher the atomic number, the higher the priority (e.g. O haspriority over C). Hydrogens attached to a chain don't count.

Rule 2: If the two atoms being compared are the same, then move to the next

atom in the chain.Rule 3: In case of a tie, double bonds count double, and triple bonds count

triple. Thus C=C has priority over C-C, but not over C-C-N


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The assignment of 1-amino-2-hydroxybutane (to the right of epinephrine in the figure

below) is straightforward, since the lowest priority group, hydrogen, is already in theback. Oxygen has priority over C-N, which has priority over C-C; thus the molecule

as shown is in the S-configuration. However, when the lowest priority group is NOT

in the back, assignment of R and S can be tricky, unless you use Woster's Steering

Wheel trick, as shown below. Consider 1-amino-1-hydroxyethan, shown in the figurebelow. In this case, H is the lowest priority group, but it is not in the back. The simple

solution is to interchange the group in the back with the lowest priority group.When two groups on a chiral center are exchanged, the resulting molecule is in the

other enantiomeric form. The priorities can the be assigned as usual, keeping in mind

that you are assigining the enantiomer of the original compound. In our example, the

prioritys are O > N > C, and so the molecule is R. This means that the original

molecule is in the S-configuration.

There are two additional forms of stereochemistry which are prevelant in drugmolecules, which are shown above. Recall that when a molecule has 2 or more chiral

centers, it can exist as diastereomers. Diastereomers are isomers which are not mirror


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images, as shown above. Diastereomers have different physicochemical properties,

and thus CAN be seperated by chromatography, fractional crystallization, or othermethods. Note that when a molecule has 2 chiral centers, ther are 4 distinct isomeric

forms. This gives rise to 2 pairs of enantiomers and two pairs of diastereomers. As

was discussed above, alkenes exhibit geometrical isomerism, and can exist in E

(trans) and Z (cis) forms.

Acid-Base Chemistry

You may recall that there are two prevailing theories that pertain to acid-base -

the Lewis acid and base theory, and the Bronsted-Lowry theory. For weal organic

acids and bases, only the Bronsted-Lowry theory is relevant. According to this theory:

A B-L acid is a compound that acts as a proton donor, and

A B-L base is a compound that acts as a proton acceptor.

It is critical to understand the chemistry of the functional groups that act as organicacids and bases, in order to be able to predict their behavior in solution. Each acid-

base equilibrium has an acid form (H:B), and a base form (B:), as shown in the

general equation at the bottom of the figure below. Recall that the degree ofdissociation of an organic acid or base is represented by the dissociation constant,

Ka, and that this is expressed as the inverse log value, pKa. Thus, the pKa value

represents the overall reaction, and not the individual acid-base forms. Either the acidor the base form can be cationic, anionic or neutral. Consider the examples below.

Acetic acid dissociates in water to set uo the acid-base equilibrium shown. Note that

the H:B form is neutral, while the conjugate base (B:) form is anionic. Conversely,

methylamine is neutral in the B: form, while theconjugate acid H:B is cationic.


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In the figure below, two acid-base equilibria are shown. In the first reaction, m-

methylphenol, with a pKa of 10.08, dissociates to form the corresponding phenolate.In this example, the H:B form is a relatively weaker acid, and the conjugate base is a

relatively stronger base. This is reflected in the high pKa value, and indicates that the

equilibrium would lie to the left at neutral pH. In the second example acetic acid, with

a pKa of 4.75, is a relatively stronger acid, and the conjugate base is a weaker base.This indicates that the compound would favor the B: form at neutral pH, and this is

reflected by the lower pKa value.

In the next figure, two H:B forms are shown which have the same pKa. Recall fromour discussion above that phenols are weak acids and amines are weak bases; however

each compound has a B: and H:B form, as shown. m-Methylphenol is a molecular

acid, meaning that it has a neutral charge. In this form, it is poorly water soluble. Ifyou treat this compound with aqueous base, it ionizes to the phenolate form. Since this

form is anionic, it is now water soluble. The second compound, N-methylpiperidine,

is a cationic acid (i.e. it is positively charged), and in this form it is water soluble.Treatment of this compound with aqueous base produces amolecular conjugate base,

which is no longer water soluble.


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Acid-base reactions can be quantitated using the Henderson-Hasselbach Equation,shown below. The equation is used to determie the percent ionization for a given

acid-base pair.

When calculating percent ionized values, it is necessary to determine whether the B:or H:B form is the ionized species. This can be readily determined from the acid-base

equation, where by convention the H:B form is on the left, and the B: form on theright. In the example below, methamphetamine, with a pKa of 9.87, is dissolved in a

solution at pH 7.87:


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In the second example, diethylbarbituric has an unionized H:B form, and an ionized

B: form. It has a pKa of 8.0, and is dissolved in fluid with a pH of 7:


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You can see more examples of this type of calculations by completing the StudyQuestions assigned at the beginning of the lecture series.

Factors Affecting Acidity and Basicity

Electronegativity. The acidity or basicity of a given functional group can be

dramatically affected by the electronegativity of neighboring groups or atoms. The

term electronegativity refers to the attraction of electrons by the nucleus of a

neighboring atom or group. There are two factors which affect the degree of

electronegativity:

1. Electonegativity increases as the distance between the nucleus and theelectron shell decreases (i.e. the atomic radius decreases).

2. Electronegativity increases as the number of protons in the nucleus increases.

Consider the upper right hand corner of the periodic table, as shown below.Electronegativity increases from left to right (increasing number of protons), and from

bottom to top (decreasing electronic radius), making fluorine the most


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electronegative atom. It should be noted that electronegativity is not a constant value

for a given atom - it depends on what the neighboring atom is, and how well it pullselectrons. For example, F next to carbon, as in ethyl fluoride, would be different than

the value for fluorine next to another atom. Also, consider acetic acid, which has a

pKa of 4.75. The alpha carbon is more electronegative when attached to 2 chlorines,

and thus the pKa decreases to 1.29. Similarly, trichloroacetic acid has a pKa of 0.65.

When a carbon is next to an electronegative atom, the carbons in neighboringpositions are subject to the inductive effect, as shown below. The electronegativechlorine in the example pulls electrons from the adjacent carbon, giving the chlorine a

partial negative charge and the alpha carbon a partial positive charge. The partial

positive charge renders the alpha carbon somewhat electronegative, and it pullselectrons from the beta carbon, making it partially-partially positive. The beta carbon

pulls electrons away from the gamma carbon, making it partially-partially-partially

positive. The inductive effect, also known as chain induction, wears off after about 3-4 carbons. For this reason, the pKa of alpha-chloroacetic acid (2.84) is lower than

beta-chloroacetic acid (4.06), and even less than gamma-chloroacetic acid (4.52).

When a group is electronegative, it is referred to as -Is. -Is groups include the


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halogens (F, Cl, Br, I), ketones, oximes and alkenes. Other strong -Is groups include

nitro, which is more electronegative than F, OR, NR2 and CR3. Groups whichare electropositive (i.e. electron releasing) include alkyl groups such as methyl, ethyl

and t-butyl.

Resonance. This concept has already been alluded to above: If the conjugate base of a

weak acid can be resonance stabilized, the acid form will be more acidic. We havealready seen this effect in carboxylic acids; resonance stabilization also occurs with

phenolic compounds, as seen below. Once the phenolate anion is formed, the negative

charge can be accomadated in one of four resonance forms. Thus the anion is

stabilized, and the phenol is a stronger weak base.


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-Is groups also have an effect on acidity and basicity. For example, the compound p-

nitrophenol (above) is more acidic than phenol itself, due to the electron withdrawing

properties of the highly electronegative nitro group. Likewise, p-methylphenol wouldbe less acidic than phenol, because of the electron releasing properties of the alkyl

group.

Biologically Significant Nitrogen Containing Compounds

As shown below, aliphatic amines are generally good weak bases in solution. As wasmentioned above, their basicity depends on the availability of the lone pair of

electrons on the nitrogen. Thus, as alkyl groups are added to the nitrogen, basicity

increases, since the alkyl groups donate electrons to the system. In water, secondaryamines are more basic than primary amines, as expected, but tertiary amines are less

basic than both. This is because of a steric effect wherin the third alkyl group reduces

the ability of the tertiary amine to H-bond. In organic solvents, tertiary are more basicthan secondary, which are more basic than primary, as would be expected.


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As seen below, aromatic amines can have unexpected acid-base properties. Consider

aniline, shown in the figure, which has a pKa of 4.6. The nitrogen in aniline has an

sp3 configuration, and as such, the lone pair of electrons can interact with thearomatic electron cloud. This effect stabilizes the B: form of aniline, and thus it is less

basic than the aliphatic counterpart, cyclohexylamine (pKa 10.6).

The nitrogen in pyridine (below left) is in an sp2 orientation, and the nitrogen is thusplanar. This means that the lone pair is in plane with the aromatic ring, and extends

out in the opposite direction. Because it protrudes from the aromatic ring, it is

available for bonding to a hydrogen. However, the lone pair is also pulled in by the

aromatic cloud, thus attenuating the basicity of pyridine. As a result, the molecule has

a pKa of 5.2.


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Pyrrole nitrogens (see above) are quite different from pyridine nitrogens. In these

compounds, the lone pair is used to complete the aromatic cloud within the molecule.Thus, the 4 pi electrons plus the two lone pair electrons add up to 6 pi electrons,

which is a Huckel number. In order to protonate a pyrrole nitrogen, the aromaticity ofthe molecule would need to be destroyed. This is, of course, energetically

unfavorable, and cannot be accomplished at physiological pH. A pyrrole nitrogen has

a pKa of -0.27.

There are two common heterocycles that contain both a pyridine and pyrrole typenitrogen, pyrazole and imidazole (above). The pyridine-type nitrogen in pyrazole has

a pKa of 2.5. Because the pyridine-type nitrogen in imidazole is sheilded from the

pyrrole nitrogen by one carbon, it has a pKa of 6.95.

There are two biologically relevant carboxylic acid derivatives which should be

mentioned, amides and amidines. As you will recall, amides (the type of bond

present in peptides) undergo a keto-enol tautomerization, as shown below. Because

the lone pair of electrons on the amide nitrogen is involved in this tautomerization, it

is not available for bonding. As a result, amides are neutral compounds, and do notundergo acid-base reactions. By contrast, the related functional group known as

an amidine is strongly basic, with a pKa in the range of 12.4. The basicity of

amidines is due to the resonance stabilization of the conjugate acid form, which

accepts a proton, and then delocalizes the positive charge as shown.


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There are two common types of acidic nitrogencompounds, sulfonamides and imides, as shown below. Because of the electron

withdrawing character of the sulfone moiety in a sulfonamide, combined with the

electron withdrawing character of the phenyl ring, the bond between the nitrogen andthe hydrogens is extremely weak. In fact, the bond is so weak that sulfonamides

dissociate in water, and donate a proton like other weak acids. A similar situation isfound in the case of nitrogens flanked by two carbonyls, a functional group known as

an imide. The alpha carbonyls are EWG, and the resulting anion is resonance

stabilized as shown, with the negative charge being distributed over 5 atoms. Thus,

imides act as weak organic acids.

Physicochemical Properties and Drug Action


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In order to elicit a pharmacological effect, drugs must be sufficiently soluble in water

to be absorbed and distributed throughout the body. They must also have sufficientlipophilicity to be able to pass through biological membranes. As was mentioned

above, the ability of an organic molecule to dissolve in water is dictated by how well

it can break into the lattice structure of water. As shown in the figure below, water has

a dipole moment, due to the 104.5 degree bond angle, and the pull of electronegativeoxygen on the attached hydrogens. This induced polarity gives water a higher boiling

point and melting point than other hydrides (e.g. H-S-H, hydrogen sulfide, is a gas atroom temperature). This dipole also allows water to hydrogen bond, and in pure

water, it H-bonds to itself, forming a lattice as shown below. Organic compounds

which ionize are readily water soluble, since they form an enevelope of water

molecules which increases the entropy of the system and decreases energy. Non-ionic, polar compounds such as those discussed above can also dissolve - they do not

dissociate, but enter the water lattice by hydrogen bonding to water.

Because drugs must encounter both aqueous and lipid environments in the body, theymust have some measure of solubility in each phase. This propensity is measured by

determining the partition ratio, which is determined using the equation below:

The partition ratio is simply the ratio of the solubility of the drug in lipid (simulatedby n-octanol) and its solubility in biological fluid (simulated by phosphate buffer at

pH 7.4). The partition ratio of a given drug will determine its solubility in plasma, itsability to traverse cell membranes, and which tissues it will reach.

A number of theoretical representations of the relationship between physicochemical

properties and drug action have been developed. One of the earliest of these is known

as the Overton-Meyer Hypothesis. This theory was developed following theobservation that neutral, lipid soluble substances have a depressant effect on neurons.


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The hypothesis states that, for these compounds, the higher the partition ratio P, the

higher the pharmacological effect. This hypothesis was expanded upon by Ferguson,who extended the theory to include all drugs. The Ferguson Principle states that the

concentration of a drug in plasma is directly proportional to its activity. This

concentration can be measured, either as molarity orpartial pressure. The Ferguson

constant X is determined by measuring the molar concentration (or partial pressure) ofa drug required for an effect, and dividing it by the molar solubility of the drug (or its

partial pressure in the pure state). As seen below, if the value of X is between 0.1 and1, the drug is said to have high thermodynamic activity. This means that the activity

of the drug is based on its physicochemical properties only, such as in a gaseous

anesthetic. Such drugs are known as non-specific agents. When the value of X is less

than 0.1, the drug is said to have low thermodynamic activity, meaning that theactivity of the drug is based on its structure rather than physicochemical properties.

Agents in this category are called specific agents, and their activity at low

concentrations infers that they have a specific receptor.

The effect of substituents on the acidity and basicity of various functional groups wasdiscussed above. This effect cab be quantified, and this was first done by Hammett,

who measured the effect of various substituents on the acidity of benzoic acid. The

derivation of the Hammett Substituent Coefficient is shown below. This coefficient(sigma) is calculated by determining the dissociation constant K for a benzoate withsubstituent X, and dividing it by the K for benzoic acid (where the substituent is H).

The log of this ratio is then the Hammett Substituent Coefficient. The values for the

Hammett Coefficient are available in tabular form, and are used in mathematicalmodels of activity known as Quantitive Structure-Activity Relationships, or

QSAR.


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In addition to contending with both lipid and aqueous environments, specific agents

must also interact with cellular macromolecules such as receptors and enzymes.Because these macromolecules are chiral, it is not surprizing that the stereochemistry

of a drug can impact its ability to bind to its target. It is possible that both enantiomers

of a given compound can have activity at the same receptor, but more often oneisomer is active, while the other is inactive. It is also possible for the "wrong" isomer

to act as an antagonist, or it may have toxic effects not seen in the "right" isomer.

Consider the drugs shown below levorphanol and dextromethorphan. Levorphanolis a powerful narcotic analgesic with a high addicition liability, and is classified as a

Schedule II narcotic. Its enantiomer (with an added but insignificant methoxy group)is dextromethorphan, which is widely used in OTC cold preparations. It has noanalgesic activity or addiction liability, but retains the antitussive action seen in

levorphanol.

The concept of isomeric potency can be generalized as outlined below. Consider a"receptor" which has three binding areas (square, round and hexagonal). When the

"right" isomer binds, it will fit precisely in all three of these sites, and this is termed

a three-point attachment. By contrast, the "wrong" enantiomer could only producea two-point attachment, and as such would be expected to be less active.


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According to this theory, the "right" isomer is called the eutomer, and the "wrong"

isomer is called the distomer. The ratio of the activities of the eutomer and the

distomer is called the eudismic ratio, as seen above, and converting the equation to

log form affords the eudismic index, EI.

Bioisosteric Replacement

Bioisosteres are functional groups which have similar spatial and electronic character.

In many cases, replacement of a group with a bioisostere results in a new compound

that retains the activity of the parent. Thus, this approach is common in thePharmaceutical industry, since it allows them to generate marketable analogues of a

known drug that has a patentable composition of matter. The figure below shows

common isosteric replacements.


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The requirement for bioisosteres to have similar spatial and electronic character isillustrated below. The phenothiazine ring system, on the left, is commonly found inantipsychotic drugs such as chlorpromazine. The phenothiazine ring is planar, due to

the two aromatic rings and the intervening sulfur, which has 4 pi electrons. If the

sulfur is replaced by a double bond, the ring retains its pi character, and the

resulting dibenzazepine retains antipsychotic activity. When the double bond is

reduced, the ring is no longer planar, as shown below left. These compounds do not

act as neuroleptics, and in fact have no CNS activity. They are mainly used asantihistamines.


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Drug-Receptor Bonding

The favorable binding of a drug to its target results in a decrease in energy, and can be

the result of multiple bonding forces. For example, the binding of acetylcholine to its

receptor involves 8 binding domains and 6 bonding modes. The most common

binding forces are shown in the figure below. The first four of these binding modesare electrostatic in nature:


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Ionic - the strongest type of non-covalent bond. This results from the

attraction of ions with opposite charges.

Ion-Dipole - results when there is an attraction between an ion and the

partial charge of a dipole of the opposite polarity.

Dipole-Dipole - Here a partially positive atom in a dipole is attracted to apartially negative atom in another dipole.

Hydrogen Bonding - A dipole-dipole interaction where on of theconstituents is a hydrogen attached to a heteroatom.

The Hydrophobic Effect - when two alkyl chains approach one another,water is extruded from the space in between them, resulting in an increase in

entropy, and thus a decrease in energy.

Charge-Transfer Complexes - a lone pair of electrons is "shared" with aneighboring group that has considerable pi character.


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Van der Waals Forces - one carbon in a chain approaches another carbonon a neighboring chain, causing a perturbation known as an induced dipole.

These opposite partial charges then attract one another.

Drugs may also bind to receptors using covalent bonding. This may be a permanent

bond, in which case the receptor or enzyme target is "killed", or it may be transient.The electrophile involved in formation of the covalent bond is generally designed into

the drug. For example, consider the nitrogen mustard shown below. The nitrogen

lone pair displaces one of the chlorides, resulting in the formation of a highly

reactive aziridine. The electrophilic aziridine then reacts with a nucleophile in theactive site, forming a covalently bonded inhibitor. The alpha-adrenergic

blockerphenoxybenzamine is an example of such a drug.

Quantitative Structure-Activity Relationships (QSAR)


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We have alluded to the fact that drug-receptor interactions are dependent on

physicochemical properties such as polarity, ionization, electron density, size,

shape and structure. A number of researchers have attempted to quantitate these

parameters, and develop mathematical models for predicting the pharmacological

activity of compounds that have not been made. This is a logical approach, since the

pharmaceutical industry is able to market only one drug for every 10,000 compoundssynthesized! The mathematical approaches developed to date are collectively known

as quantitative structure-activity relationships (QSAR).

One of the first QSAR approaches to be developed was the Hansch Linear Free

Energy Model. In this method, three parameters are measured and used in the Hansch

equation. The first of these is the substituent hydrophobicity constant, pi, which is

calculated using the first equation below. In this equation, PX is the partition

coefficient of a molecule with substituent X, and PH is the partition coefficient of theunsubstituted molecule (i.e. X = H), A more positive number indicates a more

lipophilic substituent:

The second parameter is the Hammett Coefficient, described above, and the third isthe Taft constant ES, which is a measure of steric bulk. (This is easy to remember,

since President William Howard Taft had the greatest steric bulk of all USpresidents!). These constants, which are either tabulated or calculated from tabulated

data, are then plugged into the Hansch equation (the second equation above). The

activity C is measured for 20-30 analogues, and after putting in the vaues for the threeconstants, regression analysis is used to determine a, b, c, and d. Using this equation,

it is then possible to predict the activity of unmade analogues by inserting the

appropriate constants for a given substituent and solving for c. The downside of thisapproach is that the data cannot be collected, and the values of the variable a-d cannot

be determined, until a large number of analogues has been made. Also, the approach


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only works for substitutions at one position in a parent structure, usually an aromatic

carbon.

Another approach to QSAR was developed by Free and Wilson, and later modified byFujita and Ban. This equation is also shown in the figure above. In this model, ai is the

contribution of the ith substituent to the activity of the analogue, and Xi is either 1(substituent present) or 0 (no substituent present). Again, once a large number of

analogues have been made, regression analysis is used to determine the variables a

and mu, and the equation can be used to predict activity in as yet unmade analogues.

This method has the advantage of taking more than one substituent into account for a

given molecule.

Another common method to predict activity is by the use of the Topliss Scheme, as

shown below (its pronounces towp-liss, so don't get cute!!!) By this method, an

unsubstituted aromatic ring within the parent is converted to the 4-chloro derivative.

This results in a compound that is either more active, less active, or equally active asthe parent. Let us say for the sake of an example that the 4-chloro is less active. The

Topliss Scheme would then suggest making the 4-methoxy. If the 4 methoxy is less or

equally active, the 3-chloro analogue is made. If the 4-methoxy is more active, the 4-(diethyl)amino analogue is made, and so on. Theoretically, this leads ultimately to the

synthesis of the optimally active analogue.

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