ISOQUINOLINE

ALKALOIDS AND

ALKALOIDAL AMINES

Mohammed N. Sabir, Ph.D.

March 2022

Lecture outline,

• Introduction to narcotic-analgesic compounds.

• Opiates chemistry and SAR.

• Morphine biosynthesis.

• Pharmacological effects and toxicities.

• Narcotic antagonists.

• Other related isoquinoline alkaloids.

• Alkaloidal amines and purine alkaloids.

2

Introduction to isoquinoline alkaloids…

- This class includes important therapeutic alkaloids.

- The pharmacological properties of these agents ranges from narcotic-analgesics to

central muscle relaxant, emetic agents, and antidiarrheals.

-Their wide misuse resulted in a serious global health, social, and economic negative

impacts.

-Their production is regulated by the International Agency of Narcotics (IAN).

3

Isoquinolines subclasses…

1. Morphinan class (Codeine, Morphine, Thebaine).

2. Benzyl isoquinoline class (Tubocurarine, Papaverine).

3. Protoberberine class (Berberine).

4. Emetine class (Emetine, Cephaeline).

5. Phthalide Isoquinoline class (Hydrastine).

6. Sanguinarine.

4

Important class members…

I- Ipecac, Cephaelis ipecacuanha from Brazil and C. acuminata

from Nicaragua (Rubiaceae).

The plant rhizomes and root extracts contains Cephaeline, 2/3

and Emetine, 1/3.

Induce emesis through two mechanisms,

1. Direct gastric mucosa irritation.

2. Stimulation of chemoreceptor trigger zone in brain.

The plant extract is used for gastric lavage incase of intoxications.

5

Source;https://en.wikipedia.org/wiki/Carapichea_ipecacu

anha

Their accumulation causes toxicity (proximal

myopathy and cardiomyopathy).

Emetine HCl (inj.) has antiamoebic activity and indicated in

amoebiasis as the main site of action is the GIT and Liver

and in Pyorrhea alveolaris (Rigg’s disease).

Dehydroemetine is a synthetic antiprotozoal agent.

Pyorrhea alveolaris

6

II- Tubocurarine, A water soluble quaternary alkaloid derived from the bark and stem of

Chondrodendron tomentosum, Strychnos toxifera, and S. castelnaei (Loganiaceae). The

active principle is Curarine, a non-depolarizing neuromuscular junction receptor blocker

(competitive inhibitor to acetylcholine) causing flaccid paralysis. Known as Indian Arrow

poison.

N

OH

O

N

O

OCH3

H3C CH3

H CH3

OCH3

OH

7Source;

https://en.wikipedia.org/wiki/Strychnos

Source;https://www.flickr.com/photos/plantaspeninsulaosa/6505820091

Used as skeletal muscle relaxant in,

1- Surgery.

2- Strychnine poisoning.

3- Neuropsychiatry.

4- Myasthenia gravis (diagnostic) WHY and HOW?

Available as injection (Tubocurarine chloride) and its synthetic analogues,

Pancuronium, Vecuronium, Rocuronium, Atracurium.8

Source,https://basicmedicalkey.com/skeletal-muscle-relaxants-2/

III- Opium Alkaloids (opioids) belongs to the Morphinan class, has

important economic, political, medicinal and sociological interests.

The plant is naturalized to Greece and cultivated in India (for supplying

Pharmaceuticals), Afghanistan, Turkey (for domestic uses) Iran, and China

(for domestic uses).

9

10

This class includes (Morphine, Codeine and Thebaine) extracted from the dried poppy

latex of Papaverum somniferum (Papaveraceae).

The plant is 15-60 cm of height.

Opium alkaloids show narcotic analgesic actions, frequent dosing causes physiologic and

psychic dependence (addiction) and tolerance.

Source;https://www.bbc.com/news/world-asia-37743433

Source;https://stock.adobe.com/si/search?k=opium%20poppy

Source;https://www.pbs.org/wnet/wideangle/uncategorized/from-poppy-to-heroin-step-2-

harvesting-opium/3169/

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Morphine was discovered by Freidrich Wilhelm Adam

Serturner (1783-1841).

In a series of experiments published in 1806, he

isolated an organic alkaloid compound from the

resinous gum secreted by Papaver somniferum -- the

opium poppy.

He found that opium without alkaloid had no effect

on animal models

But the alkaloid itself had 10x the power of processed

opium and named it morphine.

Source;https://en.wikipedia.org/wiki/Friedrich_Sert%C3%BCrner

In 1818, French

physician Francois

Magendie published

a paper describes

how morphine cause

pain relief and sleep

to patients.

12Source;

https://thejns.org/view/journals/j-neurosurg/108/5/article-p1038.xml

Source;

https://thejns.org/view/journals/j-neurosurg/108/5/article-p1038.xml

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At mid 1820s Morphine was widely available in Western Europe in

standardized doses from several sources, including the Darmstadt

Chemical Company started by Heinrich Emanuel Merck.

By the 1850s the injected morphine became a standard method of

reducing pain during and after surgery.

Bayer started producing this drug as an analgesic and a "sedative for cough

relief" in 1898.

Source;https://www.pinterest.com/pin/3

54869645632967803/

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An acetylated derivative of morphine demonstrated potent

analgesic property, hence called "heroic“.

The medical profession initially welcomed the new drug BUT

soon recognized its addictive potentials.

In 1913, Bayer halted production and focused on marketing

Aspirin®. Source;

https://www.pinterest.com/clambeard4680/old-medical-stuff/

Source;https://americanbusinesshistory.org/the-tortuous-saga-of-the-first-wonder-

drug-aspirin/

15

The

biosynthetic

pathway for

morphine.

Source;Robbers JE et al, 1996. Pharmacognosy and

Pharmacobiotechnology. 2ed ed.

Morphine and its analogues mimic the actions of the

endogenous neuropeptides “β-Endorphin” and “Enkephalin”.

16

Source;https://en.wikipedia.org/wiki/Beta-Endorphin

β -Endorphin

EnkephalinSource,

https://psychpedia.blogspot.com/2014/10/what-are-enkephalins.html

17

Source;https://en.wikipedia.org/wiki/Morphine

Morphine Chemistry

SAR of Morphine

CO

NCH3

H

HO

HO

Morphine

1

2

3

4

5

67

8

9

101112

1314

15 16

18

A schematic presentation for the analgesic receptor

site. Three areas are needed,

1. Flat area to accommodate a flat nonpolar

aromatic ring.

2. Cavity (pocket) to accept another series of

perpendicular ring.

3. Anionic site for polar amine group interaction.

4. Ionic part interacts with the polarized alcoholic

hydroxyl.

Source;http://chemistry.elmhurst.edu/vchembook/674narcotic.html

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δ-receptor or delta - This receptor is widely distributed in the brain and present in

the spinal cord and digestive tract. Stimulation of this receptor leads to analgesia as

well as antidepressant effects but may also cause respiratory depression and

constipation.

µ-receptors K-receptors

Analgesia, Respiratory depression,

Euphoria and dependenceAnalgesia, miosis and sedation

Brain stem and thalamus Limbic system, spinal cord

20

Pharmacological effects of morphine,

1. Constipation, is the most frequent side effect

associated with long-term opioid therapy.

2. Nausea and vomiting.

A- Ophthalmic effects, miosis.

B- Immune system effects, (k1) suppresses the

adaptive immune system through inhibiting

production of the immune mediators.

C- Gastrointestinal effects,

Source;https://sobercollege.com/addiction-blog/tell-if-someone-is-on-drugs-by-eyes/

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D- CNS effects,

Morphine and its analogues exert narcotic action manifested by analgesia, drowsiness,

changes in mood and mental clouding.

The major medical action of morphine in the CNS is analgesia.

Opiates suppress cough center which located in brainstem (medulla). Such action is

thought to underlies the use of opiate narcotics as cough suppressants.

Codeine appears to be particularly effective in this action and is widely used for this

purpose.

Morphine and Codeine

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Multiple narcotic analgesics’ dosing causes addictive physical dependence. If the drug is

discontinued, withdrawal symptoms are experienced. Although the reasons for addiction

and withdrawal symptoms are not completely known.

The c-AMP is synthesized with the aid of adenylate cyclase. Enkephalin and morphine-like

drugs inhibit the enzyme, thus decreasing the amount of intracellular cAMP levels.

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In order to compensate for the low cAMP levels, the cell express more enzymes,

accordingly, more morphine is required as an inhibitor to keep the cAMP at a low level.

This cycle will be repeated causing an elevation in the tolerance level and the amounts of

the required morphine will be more.

If morphine is suddenly withheld, withdrawal symptoms are probably caused by high

cAMP concentration, since the synthesizing enzyme “adenylate cyclase” is no longer

being inhibited, and the victim will experience the toxicities of the increased intracellular

cAMP concentration.

24

Heroin,

Heroin is synthesized from morphine by using simple esterification reaction of alcohol

and phenolic hydroxyls with acetic anhydride (equivalent to acetic acid). Heroin is much

more potent than morphine.

A possible reason may be that heroin passes the blood-brain barrier much more rapidly

than morphine.

Once in the brain, the heroin is hydrolyzed to morphine and mono-acyl morphine which

is responsible for its activity.

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Synthetic narcotic analgesic analogues include,

Meperidine (Pethidine®)

Methadone

Noscapine (Antitussive)

Dextromethorphan (Cough suppressant)

Pentazocine

Hydrocodone

Codeine

Hydromorphone

Apomorphine

Fentanyl

Methadone Meperidine

Pentazocine Fentanyl

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Narcotic Antagonists,

Agents that prevent or counteract the excessive respiratory depression caused by the

opiates administration through competition for the same analgesic receptor sites. They

are structurally related to morphine except for the nitrogen-attached group.

Nalorphine Naloxone Naltrexone

27

Nalorphine (N-allyl-normorphine) is an opioid antagonist acts at two opioid receptors,

1- Mu-receptor as antagonistic.

2-Kappa-receptors as agonist.

Used clinically to reverse opioid overdose.

Naloxone (N-allyl-noroxymorphone) is an opioid antagonist used to counteract the

effects of opiate overdose specially, the CNS and RC depressions. Used in emergency

cases of opioid overdose.

Naltrexone, an opioid receptor antagonist or weak partial agonist, used in the

management of alcohol dependence and opioid dependence.

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Using naloxone in place of naltrexone can cause acute opioid withdrawal symptoms

which lasts for 14 days;

• Sever abdominal cramps

• Diarrhea.

• Nausea.

• Vomiting.

• Agitation.

Using naltrexone in place of naloxone in an overdose can lead to insufficient opioid

antagonism and fail to reverse the overdose.

29

IV- Papaverine

Thebaine

Papaverine used for,

-IBS.

-Biliary tract spasm.

-Ureter spasm.

-Cerebral and coronary vasodilator in subarachnoid

hemorrhage and coronary artery bypass surgery.

-Papaverine may also be used as a smooth muscle relaxant

in microsurgical procedures.

30

Used in the treatment of erectile dysfunction, injected in penile tissues causing direct

smooth muscle relaxation and consequent filling of the corpus cavernosum with blood

resulting in erection.

Acts through inhibition of phosphodiesterase causing cAMP level elevation.

Toxicities include, Ventricular tachycardia,

31

Alkaloidal Amines

✓ Termed as “Protoalkaloids" or “Atypical alkaloids.”

✓ The amine nitrogen is not heterocyclic.

✓ (-)-Ephedrine is a good representative of this group.

32

Alkaloid Species Pharmacological actions

Colchicine Colchicum automnale Antimitotic, uric acid amines solvent

Ephedrine Ephedra sinica Sympathetic stimulant, bronchodilator

Cathinone Catha edulis CNS stimulant

Capsaicine Capsicum annum Circulatory stimulant

Mescaline Lophophora williamsii Hallucinogenic

Alkaloidal amines

33

Biogenetic

origin…

1-Ephedrine

2-Cathinone

3-Colchicine

4-Capsaicine

1-Ephedra "ma huang,"

The overground part of Ephedra sinica (Ephedraceae).

This plant has been used in Chinese herbal medicine for

5000 years and Introduced to modern medicine in 1923. It

is a shrub of 50-100 cm height.

In Chinese:

ma = astringent

huang = yellow

34

Source;https://www.wikiwand.com/en/Ephedra_(plant)

35

EPHEDRINE IS THE ACTIVE

PRINCIPLE IN THE PLANT EXTRACT

Ephedrine (-)-Erythro-α-[1 (methylamino) ethyl]benzyl alcohol.

Production is either by extraction from the plant or chemical synthesis.

Chemical synthesis from benzylhydroxymethyl ketone and methylamine.

Methyl amine(+)-Ephedrine

Ephedrine occur as white needle-like crystals soluble in water, alcohol, chloroform, ether

and petroleum ether.

36

Source;https://www.jimdamtrading.co.in/dry-chemical-powders.htm

The structure similarity to endogenous catecholamines is responsible for potent non-selective sympathomimetic action, stimulating both α and β-adrenergic receptors.

Ephedrine and Pseudoephedrine are mixed action adrenergic

agonists.

37

Source;http://chemistry.elmhurst.edu/vchembook/663adrenergic2.html

Adrenergic receptor-

ligand stereochemistry

needed for agonistic

action.

38

Adenylate cyclase

ATP c-AMP

PKA (c-AMP dependent PK)

Ca++

Na+

Ca++

β1-adrenergic activity α2-adrenergic activity

Pharmacologic Actions of Ephedrine

Adenylat

e cyclase

ATPc-

AMP

PKA

(c-AMP dependent PK)

Ca++

Na+

Ca+

+

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Medicinal uses (Ephedrine sulfate and Ephedrine. HCl)…

o Bronchodilator.

o Allergy.

o Cough suppressant.

o To increase BP during shock.

o Vasoconstrictor.

o Decrease inflammation and mucus secretion.

40

Ephedrine and weight loss

Source;https://www.plantbasednews.org/lifestyle/plant-based-diet-weight-loss-slashes-diabetes

Available as (Ephedrine sulfate& Ephedrine HCl)

Pharmaceutical dosage forms;

1-Tablets

2-Oral liquid dosage forms

3-Inhalations

4-Injections

Clinical uses:-

1- Allergic disorders.

2- Common cold.

3- Cough preparations.

4- Asthma.

5- Nasal congestion.

41

Overdose and drug interactions…

1- Hypertension

2- Headache

3- Dizziness

4- Palpitation

5- Vomiting

6- Nervousness (CNS effects)

42

Ephedrine

Toxicities

Ephedrine derivatives with

less α-receptor affinityN-MethylephedrineNorephedrine

Mescaline

• Obtained from the

plant cactus.

• Lophophora

williamsii, (Cactaceae)

• A CNS stimulant

(hallucinogenic) agent

43

Source:

https://weberseeds.nl/eshop/en/Plants/Lophophora-williamsii-Peyote-plants::162.html

Medicinal uses,

• For alcoholism.

•Depression.

•Research

44

Source,https://europepmc.org/article/med/30318013

KHAT, Catha edulis (Celastraceae)…

o A native tree to tropical East Africa.

o The principal alkaloid “Cathinone” is concentrated in the plant leaves.

o The fresh leaves contains more alkaloids compared to the old ones,

which contains the less active metabolite (+)-norephedrine.

o The leaves are chewed habitually by the locals.

o The alkaloid inhibit hunger and fatigue sensations.

45

Source;http://pza.sanbi.org/catha-edulis

Source;https://www.prota4u.org/database/protav8.asp?g=ps

k&p=Catha+edulis

Source;https://www.prota4u.org/database/protav8.asp?

g=psk&p=Catha%20edulisphenylalkylamine alkaloid (-)-cathinone.

Cathinone actions are analogues to (+)-amphetamine including:-

Induction of catecholamine release from storage sites (CNS stimulant action).

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Psychological effects include,

Euphoria, anxiety, increased libido, alertness, concentration,

self-confidence, sociability, irritability, aggression,

psychomotor agitation, repetitive and obsessive behavior,

paranoia.

At chronic and/or high doses, amphetamine psychosis can occur.

COLCHICINE

Is the dried ripe seed of

Colchicum automnale

(Liliaceae)

47Source;https://plantsam.com/colchicum-autumnale/

• Colchis = refers to plant flourish.

• Autumnale = refers to the Season where the plant bloom.

• The plant is indigenous to Europe and North Africa

• The Arabs recommended the use of the corn for Gout.

• Colchicum contains the Colchicine (0.6-0.8%).

Chemistry…

No reaction with weak acids, why?

48

Gout Pathophysiology

• Uric acid is the end-product of purine metabolism.

• Urate-oxidase (Uricase) degrades uric acid (UA) to allantoin “more water soluble”.

49

Uric acid accumulation cause hyperuricemia (SUA < 7mg/dl in men, and > 6mg/dl in

women), hyperuricemia cause gouty arthritis (through the deposition of monosodium

urate crystals in articular and extra articular tissues).

Hyperuricemia as an independent risk factor for metabolic syndrome, coronary artery

disease and chronic kidney disease.

50

- Reduction in lactic acid production.

- Less deposition of uric acid.

- Leucocyte migration inhibition.

- Decrease phagocytosis “less inflammation”.

The mechanism of action

51

Mitosis affected

by colchicine

52

Source;https://www.toppr.com/ask/question/colchicine-results-in-doubling-of-chromosome-number-because-of/

Capsaicin…

• Derived from Capsicum annuum (Solanaceae) also called

“Chili pepper”.

• Used topically as circulatory stimulant and analgesic for

arthritis , neuropathy, neuralgia, and as a local anesthetic.

• Also used in psoriasis to decrease itching and inflammation.

53

Source;https://www.freepik.com/free-photo/sweet-chili-

peppers-capsicum-annuum-illustration-from-medical-botany_3540051.htm

• It binds selectively to capsaicin receptors (CR) located on the membranes of pain

and heat-sensing neurons.

• CR are a heat-activated calcium channel proteins that opens between 37–45 °C .

• Upon binding, it causes the channel to open below 37 °C, which is why capsaicin is

linked to the heat sensation.

• Prolonged activation causes presynaptic substance P depletion.

• Neurons that devoid from CR will be unaffected.

• A previous study in 2003 reported that capsaicin regulates blood sugar

levels through carbohydrate breakdown activation after meals.

54

Oil of Capsicum

Oil of Capsicum derived from chili pepper (Capsicum spp.)

Medicinal uses,

1- Analgesic (topical ointments, dermal patches) in

concentrations 0.025-0.25%.

2- In nasal sprays as decongestant anti-inflammatory.

3- In arthritis.

4- Neuralgia.

5- Reduce itching and inflammation (as creams in

psoriasis).55

Source;https://www.exportersindia.com/maluba-essential-

oils/capsicum-oil-3457971.htm

56

Class Example Species Pharmacological actions

Purine alkaloids

Caffeine Coffea arabica CNS stimulant

Theophylline Thea sinensis Bronchodilator

Theobromine Theobroma cacao Vasodilator

Steroidalalkaloids

Solanine Solanum spp. Anti-inflammatory

Veratrine Veratrum album Antihypertensives

Terpenoidalalkaloids

Aconitine Aconitum spp. Antipyretic, analgesic, neurotoxin

Pseudoalkaloids

Purine bases

- Include alkaloids derived from imidazole ring, the nucleotides

(xanthine bases).

Those which retain therapeutic activities are:-

1-Caffeine (1,3,7-trimethylxanthine)

2-Theophylline (1,3-dimethylxanthine)

3-Theobromine (3,7-dimethylxanthine)

57

58

• A purine alkaloid belongs to xanthine class.

• White crystalline powder with bitter taste.

• Caffeine is found in varying quantities in the seeds, leaves, and fruit of some

plants like (Camelia sinensis, Coffea arabica, Coffea robusta) (Theaceae,

Rubiaceae)

Source;https://www.plant-world-

seeds.com/store/view_seed_item/7048

Source;https://onszaden.com/coffea_arabica

1- Caffiene

59

Source;https://www.quora.com/What-are-the-negative-effects-if-any-of-long-term-caffeine-consumption

Source;https://en.wikipedia.org/wiki/Caffeinism

60

Over-the-counter medications Service size Caffeine content (mg)

NoDoz (maximum strength)® 1 tablet 200

Vivarin® 1 tablet 200

Excedrin® 2 tablets 130

Anacin (maximum strength) ® 2 tablets 64

Caffein concentrations in various pharmaceutical products.

Theophylline

Theobroma cacao and C. sinensis

Theobromine

Theobroma cacao

61

Other purine alkaloids used as bronchodilators through competitive

nonselective phosphodiesterase inhibition, thereby increasing intracellular

c-AMP, and inhibiting TNF-α and leukotriene synthesis, thus reducing

inflammation and innate immunity

They are also nonselective adenosine receptor antagonists. Act by antagonizing A1, A2,

and A3 receptors, which are responsible for the cardiac effects of these agents.

Thank you

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