Alkaloids – Natural nitrogenous
secondary metabolites from plants
and microbes
Some important classes of alkaloids
Class
Piperidine alkaloids
Pyrrolidine/tropane
alkaloids
Precursors
L-lysine (C5N)
Pyridine alkaloids
L-Trp or L-Asp
Examples
Piperine
_____________
L-ornithine (C4N) Cocaine, scopolamine
Niacin (Vit. B3), nicotine
Catecholamines
L-Tyr (C6C2N)
and tetrahydroisoquinolines
Opiates
2 L-Tyr units
Dopamine, adrenaline, mescaline
anhalamine
Morphine, tubocurarine
Phenylalanine-derived
L-Phe (C6C3N)
Capsaicin, ephedrine
Indole alkaloids
Quinoline alkaloids
Purine alkaloids
L-Trp
“
L-Gly, L-Gln, L-Asp
Serotonin, ergotamine, LSD, vinblastine
quinine, camptothecin
Caffeine, theobromine
Building blocks from the acetate, shikimate, or deoxyxylulose phosphate pathways are also
frequently incorporated into the alkaloid structures.
Many alkaloids acquire their N via transamination reactions (catalyzed by Vitamin B6).
Most alkaloids are quite toxic and produced by the plant as a defense against herbivores.
Key biological activity of alkaloids: interaction with CNS
• Most of the biological effects of alkaloids are due to their similarity
to neurotransmitters in the human body.
• They can either mimic or block the effects of neurotransmitters, or
cause fluctuations in the normal levels of neurotransmitters.
• This leads to numerous physiological and psychological effects
Role of neurotransmitters: to transmit nerve impulses across the
synapse (space) between neurons in brain, nervous system
Structures: mostly small molecules containing amino or ammonium
functionalities
Action: They are released from nerve endings and bind to receptors
on the surface of another neuron in the network
Agonists bind to and stimulate receptors
Antagonists block receptors
Not all alkaloids affect CNS, but many do!
Neurotransmitters that have effects on mood,
thought processes
(a catecholamine)
(an indole, aka 5-hydroxytryptamine or 5-HT)
Parkinson’s disease – dopamine transmission is inadequate, can be improved by L-DOPA
Depression – treatment with SSRIs increases dopamine in the synaptic cleft
Neurotransmitters that control physiological effects
throughout the body
a catecholamine
a catecholamine
a quarternary ammonium salt
Norepinephrine malfunction is implicated in anxiety and mood disorders, bipolar disorder
Acetylcholine: low levels may cause memory lapses associated with Alzheimers’, can be
improved with cholinesterase inhibitors
Alkaloids derived from lysine
(piperidine alkaloids – C5N)
Formation of the 6-membered ring
(also see Lobelia)
Formation of piperine: C6C3 unit is lengthened
and linked with 2o amine to form amide linkage
Piperine: from black pepper (Piper nigrum)
Spicy flavor and CYP3A4 inhibitor
The pungency of piperine is caused by activation
of the heat and acidity sensing TRPV ion channel
found on nociceptors (pain sensing nerve cells)[
Has insecticidal properties
Produced from three different building blocks
Tropane alkaloids (Solanaceae family)
Formation of first ring
(pyrrolidine ring)
• Tropanes are bicyclic non-aromatic alkaloids. They are not common in edible
plants, but are found in some botanicals and medicinal herbs.
• The most common natural tropane alkaloids are (-)-hyoscyamine and (-)scopolamine (also known as hyoscine). High concentrations of these alkaloids have
been found particularly in Datura species.
• Hyoscyamine is the major alkaloid in most parts of Datura stramonium (thorn
apple or Jimson weed); scopolamine is the major alkaloid in other Datura spp.
Assembly of the
tropane skeleton found
in cocaine, hyoscyamine
Chain building by acetyl Co-A units leads to
second ring in bicyclic tropanes
From leaves of Erythoxylum
coca. Well-known CNS
stimulant, also anaesthetic
Extracts of coca leaves
used in original Coca-cola
recipe (cola provided the
caffeine) but in 1906 the Coca
was eliminated.
Structural similarity to
acetylcholine allows tropanes
to block muscarinic ACh
receptors, providing
anaesthetic effect.
Found in belladonna
(Atropa belladonna),
henbane and Datura species
Can be used as sedative
or external pain relief, but
they are toxic and have
psychotropic effects
(hallucinations, etc.)
Effects of tropane alkaloid contamination in animal feed
From European Food Safety Authority website
http://www.efsa.europa.eu/EFSA/efsa_locale-1178620753812_1211902036472.htm
• “Tropane alkaloids” are a group of > 200 compounds best known for their
occurrence in the family Solanaceae, comprising over 100 genera including
Datura.
• Datura plants are toxic for animals if ingested in large amounts. Their
seeds contain significant amounts of hyoscyamine and scopolamine, and
can be found as botanical impurities in feed materials, particularly in
soybean and linseed products.
• Reports on adverse health effects in
animals refer mostly to accidental
intoxications following the consumption of
Datura plants rather than to the
contamination of feed.
• Overall, pigs have been shown to be
among the most sensitive species to Datura
poisoning.
Effects of tropane alkaloid contamination in animal feed
(cont’d)
From European Food Safety Authority website
http://www.efsa.europa.eu/EFSA/efsa_locale-1178620753812_1211902036472.htm
• As competitive antagonists for muscarinic acetylcholine receptors,
tropanes prevent binding of acetylcholine, thus affecting the function of
smooth muscles and exocrine gland cells, heart rate, respiration and
functions in the CNS.
• Most common symptoms reported: dryness of the mucosa in the upper GI
and respiratory tract, constipation and colic (in horses), pupil dilation,
alterations in heart rate, and CNS effects such as restlessness, irritability,
ataxia, seizures and respiratory depression.
• Tropane alkaloids are readily absorbed following oral ingestion, but have a
short biological half-life and are rapidly biotransformed or excreted.
• Exposed animals are likely to exhibit symptoms and be removed from the
food supply, therefore, it is unlikely that residues of tropane alkaloids in
edible tissues, milk and eggs constitute a risk for consumers.
More on tropanes...belladonna &
henbane
Background and Occurrence
• Atropa belladonna is known as Deadly nightshade
• Related to the tomato (also a member of Solanaceae)
• Native to: Europe, North Africa, Naturalized in North America
• Morphology: Branching herbaceous perennial, berry bearing,
~1.5m tall
• It’s highly toxic! All parts of the plan contain tropane alkaloids
atropine and hyoscyamine. Berries are sweet, but toxic
• Historical use: Ladies “at court” in Europe applied to the
eyes to dilate pupils, “enhance beauty”
• Anticholinergic agent: Causes ataxia (loss of coordination)
• Also causes pupil dilation, double vision, increased body
temperature, confusion. Competes with ACh, reversibly inhibits
neuron activity
Medicinal Uses of Atropine
Antitoxin for cholinesterase Inhibitors
ie: physostigmine, neostigmine
Organophosphate insecticides
Cosmetic application to eyes
Gastrointestinal sedative (for antacids)
External pain relief (root preparation)
Henbane & Jimson weed also contain tropanes
Henbane (Hyosycamus niger) contains
primarily hyoscyamine, a stereoisomer
of atropine, and scopolamine (-)hyoscine.
Henbane was thought to induce
hallucinations & visions of flight,
associated with witches. Could be used
to treat GI spasms if it wasn’t so toxic.
Jimson weed (Datura) grows wild
throughout Europe, Americas.
Thieves used it in the Middle Ages to
drug & rob people.
Some South American tribes used it to
calm down unruly kids due to mild
sedative effect at low doses.
Henbane
Cocaine
• From Erythroxylum coca
• Historically, field workers
would consume while
picking the leaves
• Leaves were extracted with
gasoline, then acidified with
aqueous acid to purify out
the cocaine HCl salt
• Salt converted back to “free
base” by using CaCO3
• Ether solution of free base
evaporated down -> crack
Cocaine has several physiological & psychological effects:
• Stimulant: increases norepinephrine release
• Anesthetic: binds to acetylcholine receptors, decreases Na+ transport
• Mood-enhancing/addictive: increases dopamine levels by blocking reuptake
Synthetic analogues of cocaine used as local anaesthetics
have muscarine structural motif:
procaine/novocain
Local anaesthetic used to
numb skin, rapidly absorbed.
Also used as anti-arrhythmia
agent after a heart attack
Alters signal transduction in
nerve membranes by blocking
fast voltage-gated sodium
channels, stopping pain signals
Used mainly as a
topical anaesthetic
Found in anbesol,
cepacol, solarcaine
Both are sodium channel
blockers, used mainly in
dentistry
Cocaine and addiction
• Addiction from cocaine and similar
drugs arises from its effects on
dopamine transmission.
• Normally, dopamine is released
from the transmitting neuron, crosses
the synapse and binds to receptors on
the receiver.
• Excess dopamine is transported
back to the transmitting neuron.
• Cocaine blocks the dopamine
transporters, inhibiting the re-uptake
of dopamine by the transmitter.
• This results in increased dopamine
levels in the synapse  euphoria
• Reward system results in addiction
• Users get used to higher levels of
dopamine and “crash” when stimulus
is removed.
It’s the real thing...
• Cola (kola) is the dried cotyledon from seeds of Cola spp.
(Sterculiaceae), e.g. C. nitida & C. acuminata, trees cultivated
mainly in West Africa and the West Indies.
• Fresh cola seeds are chewed in tropical countries as a stimulant
• Cola seeds (nuts) contain up to 3% caffeine & 0.1% theobromine,
partly bound to tannins. On drying, some polyphenol oxidation
occurs, forming a red pigment, and free caffeine is liberated.
• Vast quantities of dried seeds are processed for the preparation
of cola drinks, e.g. Coca-Cola and Pepsi-Cola.
• Coca-Cola was invented by Atlanta pharmacist John Pemberton in
1886. It originally contained cocaine (from E. coca leaf) and
caffeine from the kola nut (5 oz. coca leaf/gallon of syrup). It once
contained ~ 9 mg cocaine per glass, but in 1903 it was removed.
• After 1904, Coca-Cola started using "spent" leaves left over from
the cocaine-extraction process. A cocaine-free coca leaf extract is
still used for flavoring.
Alkaloids from shikimate precursors
via transamination
Capsaicin
• Produced by red hot chili peppers (Capsicum
annuum) of Solanaceae
• Secondary metabolite, probably produced as a
deterrent against herbivores & fungi
• Has analgesic properties
• Used medicinally in creams to treat neuralgia
or neuropathy caused by diabetes, herpes
• Also in topical pain-relieving preparations for
arthritis.
• The initial burning effect of capsaicin affects
the pain receptors, depleting substance P, and
making them less sensitive
Nicotinic acid/Niacin (Vit. B3)
•
•
•
•
•
•
Role: redox cofactor when in form of NAD(P)+/NAD(P)H
In animals, produced by degradation of L-Trp
In most plants, L-Asp is the precursor
Nuc. attack on phosphoglyceraldehyde followed by imine formation
Reaction with N-methyl pyrrolinium leads to nicotine
Nicotinic acid is also produced during the roasting of coffee from
the decomposition of N-methyl derivative trigonelline
Structural similarity with acetylcholine
leads to stimulant properties
Tobacco - the cured and dried leaves of Nicotiana tabacum (Solanaceae)
an annual herb indigenous to tropical America, cultivated widely for smoking
Tobacco leaves may contain from 0.6–9% of (−)-nicotine (an oily, volatile liquid)
together with smaller amounts of structurally related alkaloids. Nicotine in
small doses can act as a respiratory stimulant, but in larger doses it causes
respiratory depression.
Arecoline is the major alkaloid in Areca nuts (betel nuts) - the seeds of Areca
catechu (Palmae/Arecaceae), a tall palm cultivated in India & other parts of
Asia. Nuts are mixed with lime, wrapped in leaves of the betel pepper and then
chewed for their stimulant effect, and subsequent feeling of well-being and
mild intoxication.
Addition of a C6C2
unit on each side of
amine group leads
to lobeline
Lobelia inflata or “Indian tobacco” contains lobeline, which has a
similar but weaker stimulant effect than nicotine
Used in smoking deterrent preparations
Alkaloids derived from tyrosine, Part 1:
Catecholamines
Peyote:
The dried sliced tops of Lophophora
williamsii, found in Mexico &
Southwestern US is used to prepare
peyote, used by native Americans in
religious ceremonies to induce
hallucinations. The major
psychoactive alkaloid in peyote is
mescaline, named after the
Mescaleros Apaches. Mechanism of
action may involve blocking reuptake
of norepinephrine at receptors,
increased serotonin release.
Cacti have been around since
prehistoric times...
• Journal of
Ethnopharmacology
study documented
prehistoric peyote use!
• El Seedi, et al, 2005
• More info in a separate
slideshow.
Analyzing ancient alkaloids…
• Two peyote buttons (Lophophora) found in a TX cave in 1933 were
obtained from Witte museum for the study
• Insides were scraped to give a powder that was either extracted
with EtOH, basified and further extracted with CHCl3 OR boiled with
10% HCl, extracted with ether.
• Dried extracts of 2-14 mg were obtained
• Dragendorff test showed alkaloids were present (about 2% by
mass)
• TLC and GC-MS analysis confirmed mescaline present (isoquinoline
alkaloids not found)
• Radiocarbon dating analysis showed the samples to be from 37803660 BCE.
• Oldest artifact proven to contain a psychoactive substance!
(El-Seedi, et al, J. Ethnopharmacology (2005)101: 238-242.)
Those wacky cacti! Family: Cactaceae
Genus/species: Lophophora williamsii
Carnegiea gigantea
Many cactus alkaloids have a heterocyclic
6-membered ring (isoquinoline structure):
Adrenergic receptors
• a-adrenergic receptors:
– a1 – blood vessels, causes vasoconstriction
– a2 – nerves, mediates synaptic transmission
• b-adrenergic receptors:
– b1 – heart, cerebral cortex, agonists increase heart
muscle contraction
– b2 – lungs, cerebellum, agonists dilate bronchi
– b3 – adipose tissue, agonists increase lipolysis
• General: increases cyclic AMP, activating protein
kinases
“Beta blockers”: synthetic antagonists
of b-adrenergic receptors
and some agonists
Block b-adrenoreceptors that regulate cardiac
muscle contractions (b1) and smooth muscle
relaxation in the lungs (b2)
Inhibits
DOPA
decarboxylase
cardiac stimulant
b1 agonist
a1 agonist
vasoconstrictor, used in Afrin
nasal spray (natural)
b1 antagonist
controls force
of heart
contractions,
lowers bp
a1 antagonist
vasodilator
lowers bp
b2 agonist relaxes
bronchial smooth
muscle (asthma)
Used since 1500’s
--CNS Stimulant
--Epinephrine Agonist
--Bronchodilator
--Decongestant
--Diet Aid
BANNED!
Catecholamine mimics from L-Phe
The major stimulant in
Ephedra is ephedrine,
a sympathomimetic
amine (similar effects
to noradrenaline)
Unlike actual
catecholamines,
ephedrine only acts
weakly on receptors,
but it can displace
noradrenaline from
nerve storage vesicles
which then stimulates
receptors.
Ephedrine is orally
active and lasts longer
than noradrenaline.
“Khat” Catha edulis (Celastraceae): In African and Arabian countries,
the leaves of this tree are chewed as a stimulant to alleviate hunger
and fatigue, while also giving a sensation of general well-being. Users
become cheerful and talkative, so khat has become a social drug and
use may lead to psychological dependence.
Young, fresh leaves are most effective. The principal CNS stimulant is
contain (−)cathinone ,with similar pharmacological properties as the
synthetic CNS stimulant (+)-amphetamine.
Both compounds act by inducing release of catecholamines.
Amphetamines usually cause
dependence in users.
Other amphetamine-like
derivatives include MMDA
(methoxymethylenedioxyamphet
amine) and MDMA (methylenedioxymethamphetamine)
MMDA may be formed in the
body after ingestion of nutmeg
(Myristica fragrans) by an
amination process on myristicin,
which may account for reported
euphoric and hallucinogenic
effects of consuming nutmeg.