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/
11
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
13
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/
14
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
19
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/
21
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
22
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.
23
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.
25
Synthetic narcotic analgesic analogues include,
Meperidine (Pethidine®)
Methadone
Noscapine (Antitussive)
Dextromethorphan (Cough suppressant)
Pentazocine
Hydrocodone
Codeine
Hydromorphone
Apomorphine
Fentanyl
Methadone Meperidine
Pentazocine Fentanyl
26
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.
28
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+
+
39
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).
46
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
62
Top Related