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Alkaloids
1. INTRODUCTION, CHEMISTRY AND PHARMACOLOGICAL ACTIVITY
OF ALKAOIDS
DEFINATION- Alkaloid, any of a class of naturally occurring
organic nitrogen-containing bases. they are called as alkali
like substances.
Other compounds like amino acids proteins, nucleic
acids also contain nitrogen but they are not alkaloids
This group also includes some related compounds with
neutral and even weakly acidic properties. Some synthetic
compounds of similar structure are also termed
alkaloids. In addition to carbon,hydrogen and nitrogen,
alkaloids may also contain oxygen, sulfur and, more rarely,
other elements such as chlorine,bromine,
and phosphorus.
2. Alkaloids have diverse and important physiological effects
on humans and other animals. More than 3,000 different
types of alkaloids have been identified in a total of more
than 4,000 plants species.
Alkaloids are often divided into the following major
groups
1. True alkaloids" contain nitrogen in the heterocycle and
originate from amino acids. examples are atropine,
nicotine, and morphine.
2. Pseudoalkaloids – alkaloid-like compounds that do not
originate from amino acids. This group includes terpene-
like and steroid-like alkaloids, as well as purine-like
alkaloids such as caffine, theobromine and theophyline.
3. Properties
In their pure form most alkaloids are colourless, non-
volatile, crystalline solids. Many alkaloids dissolve poorly
in water but readily dissolve in organic solvents.
Alkaloids and acids form salts of various strengths.
These salts are usually freely soluble in water and ethanol
and poorly soluble in most organic solvents. Exceptions
include scopolamine hydrobromide, which is soluble in
organic solvents.
Most alkaloids have a bitter taste or are poisonous
when ingested. Alkaloid production in plants appeared to
have evolved in response to feeding by herbivorous
animals; however, some animals have evolved the ability
to detoxify alkaloids.
4. ATROPINE
Source-Atropine is found in many members of the
solanaceae family. The most commonly found sources are atropa
belladonna, datura innoxia,D.metel and D.stramonium.
Introduction: Atropine a naturally occurring alkaloid of
"atropa belladonna” is a competitive antagonist of
muscarinic cholinergic receptors. It is absorbed from the
gastro-intestinal tract, and is excreted in the urine.
Atropine undergoes hepatic metabolism and has a plasma
half-life of 2-3 hours. Atropine ampoules should be stored
away from light and never is frozen.
Mechanism of action: Blocks the action of acetylcholine at
parasympathetic sites in smooth muscle, secretory glands
and the CNS; increases cardiac output, dries secretions,
antagonizes histamine and serotonin.
5. Indication:
• as an antisialagogue when reduction of secretions of the respiratory
tract ; its routine use as a preanesthetic agent
• to reduce the increased vagal tone (decreased pulse and blood
pressure) produced by intra-abdominal traction or ocular muscle
traction, its routine use to prevent such events is discouraged,
• to temporarily increase heart rate or decrease AV-block until
definitive intervention can take place,
• as an antidote for overdose of cholinergic drugs or for
cholinesterase poisoning such as from organophosphorus
insecticides
• as an antidote for the “rapid” type of mushroom poisoning due to
the presence of the alkaloid, muscarine, in certain species of fungus
such as Amanita muscaria, and
• to alleviate the muscarinic side effects of anticholinesterase drugs
used for reversal of neuromuscular blockade.
6. Chemistry and pharmacology
Atropine is Tropane alkaloids
Atropine is an enantiomeric mixture of d-
hyoscyamine and l-hyoscyamine, with most of its
physiological effects due to l-hyoscyamine. Its
pharmacological effects are due to binding to muscarinins
acetylcholine receptors. It is an antimuscarinic agent. The
most common atropine compound used in medicine is
atropine sulfate.
8. QUININE
Source- Cinchona ledgeriana , Cinchona calisaya,
Cinchona succirubra, Cinchona officinalis Linn . family-
Rubiaceae
Constituents
- About 30 alkaloids have been isolated from the
cinchona bark; four are considered important:
quinine, cinchonine, quinidine, and cinchonidine.
- Cinchona bark is well-known source of quinine used
as a cure for malaria.
Quinine is Quinoline alkaloids
9. antiparasitic activity-
It is used as an antimalarial drug
Quinine acts primarily on the erythrocytic stage of human malarias
with little parasiticidal effect on sporozoites, hepatic stages, or
gametocytes of P. falciparum.
The asexual stages of P. ovale are the most vulnerable to quinine,
followed by P. vivax, P. malariae and then P. falciparum. Quinine has
some gametocytocidal activity for P. vivax and P. malariae,
mechanism of action
The mechanism of action is interference with the parasite’s ability to
digest haemoglobin. Quinine and quinidine also inhibit the
spontaneous formation of beta-haematin (haemozoin or malaria
pigment) which is a toxic product of the digestion of haemoglobin by
parasites.
Quinine is also a mild antipyretic and analgesic and has been used
in common cold preparations for that purpose
11. RESERPINE
Reserpine is isolated from roots of Rauwolfia serpentina
(Sarpagandha) also know as Black snakeroot or Indian
snakeroot or devil pepper.
family-Apocynaceae
Reserpine is an indol alkaloid
It is antipsychotic, and antihypertensive drug that has
been used for the control of high blood pressure and for
the relief of psychotic symptoms.
The antihypertensive actions of reserpine are a result of
its ability to deplete catecholamines(adrenaline,
noradrenaline, and dopamine) from peripheral
sympathetic nerve endings. These substances are normally
involved in controlling heart rate, force of cardiac
contraction and peripheral vascular resistance.
12. Mechanism of action
Reserpine irreversibly blocks the vesicular
monoamine transpoter (VMAT). This normally
transports free
intracellular noradrenaline,serotonin
and dopamine in the presynaptic nerve terminal
into presynaptic vesicles for subsequent release
into the synaptic cleft.
14. MORPHINE
Morphine is isolated from Papaver somniferum, commonly
known as the opium poppy, family papaveraceae
Morphine is a pain medication. It can be taken for both acute
pain and chronic pain. It is frequently used for pain from
myocardial infraction and during labour. It acts directly on the
CNS to decrease the feeling of pain. Morphine acts by
engagement in cell surface opiate receptors (predominant µ type
receptors) that are found in the central nervous system, but also
heart, lung, vascular and intestinal cells.
Its duration of analgesia is about three to seven hours
Morphine has a high potential for addiction and abuse. If the
dose is reduced after long-term use, withdrawal symptoms may
occur. Common side effects include drowsiness, vomiting, and
constipation.
17. PAPAVERINE
papaverine is isolated from Papaver somniferum, commonly known
as the opium poppy, family papaveraceae
Papaverine is an opium alkaloid. it is antispasmodic drug due to
its smooth muscle relaxant effect , used primarily in the treatment
of visceral spasm and vasospasm (especially those involving the
intestines, heart, or brain), and occasionally in the treatment of
erectile dysfunction.
It is a direct-acting smooth muscle relaxant used in the treatment
of impotence and as a vasodilator, especially for cerebral
vasodilation.
Papaverine is Isoquinoline alkaloids
19. EPHEDRINE
It is obtained from the dried tender stems of the Chinese
wonder drug Ma Huang
It occurs in Ephedra Gerardiana; Ephedra
sinica ; Ephedra equisetina ,family - Ephedraceae
Amino alkaloids e.g., Ephedrine;
Both ephedrine and pseudoephedrine increase blood
pressure and act as bronchodilators, with
pseudoephedrine having considerably less effect.
Ephedrine promotes modest short-term weight loss
It works mainly by increasing the activity
of norepinephrine (noradrenaline) on adrenergic
receptors.
20. As a phenethylamine, ephedrine has a similar chemical
structure to amphetamine (psychoactive addictive
substance) . Because of ephedrine's structural similarity to
methamphetamine, it can be used to create
methamphetamine.
chemistry -Ephedrine exhibits optical isomerism and has
two chiral centres, giving rise to four stereoisomers. By
convention, the pair of enantiomers with the
stereochemistry (1R,2S) and (1S,2R) is designated
ephedrine, while the pair of enantiomers with the
stereochemistry (1R,2R) and (1S,2S) is called
pseudoephedrine.
In the outdated D/L system (+)-ephedrine is also referred
to as D-ephedrine and (−)-ephedrine as L-ephedrine
21. Mechanism of action
Ephedrine, a sympathomimetic amine, acts on part of the
sympathetic nervous system (SNS). The principal
mechanism of action relies on its indirect stimulation of
the adrenergic receptor system by increasing the activity
of noradrenaline at the postsynaptic α and β receptors.
24. Ergot alkaloids
Ergot is a fungal infection that has infected rye
and other plants since farming began.
One of the constituents of ergot, the ergot
alkaloids, were found to have useful medicinal
properties.
Ergot was known to cause gangrene in the
limbs of those who had ingested infected bread.
But later its first medicinal property as a
powerful oxytocic (facilitating childbirth) was
discovered, and more recently its derivatives
have been used in the treatments of migraine.
25. Ergot is the dried sclerotium of the fungus Claviceps
purpurea, which can arise in the ovary of the rye Secale
cereale. These sclerotia can replace one or more of the
kernels in a mature grain head with a hard, dark coloured,
horn-like mass .
Although ergot most readily attacks rye it can also infect
other wild and cultivated cereals (barley, wheat, oats),
and other grasses. These sclerotia contain the fungal
toxins and are harvested along with the rest of the grain so
that the ergots contaminate the food chain.
Widespread contamination by ergot, known as
ergotism, occurred frequently during the Middle Ages.
27. Ergot alkaloids may be classified into amine alkaloids, peptide
alkaloids and those containing non specific constituents.
1.Amine alkaloids
6-methyl ergoline
lysergic acid
lysergic acid diethylamide (LSD)
Ergometrine
methysergide
2.Peptide alkaloids
ergotamine
alpha – ergocryptine
bromocriptine
3.Non-specific constituents
Acetylcholine
histamine
tyramine
28. Composition of ergot
The ergot sclerotium contains up to 30-40% of fatty oils and up to 2%
of alkaloids
Table 1. Alkaloids of the ergot sclerotium
Group Alkaloid Formula
1.Ergometrine
group
Ergotmetrine
Ergotmetrinine C19H22O2N3
Ergotamine
C33H35O5N5
2.Ergotamine
group
Ergotaminine
Ergosine
C30H37O5N5Ergosinine
Ergocristine
C35H39O5N5
3.Ergotoxine group
Ergocristinine
Ergocryptine
C32H41O5N5Ergocryptinine
Ergocornine
C31H39O5N5
Ergocorninine
29. Chemistry
ergot alkaloids are indole compounds that are
biosynthetically derived from L-tryptophan . Over
80 different ergot alkaloids have been isolated, A
common portion of the ergot alkaloids is a
tetracyclic ring system .
Ergot alkaloids may be conveniently divided into
three major structural groups: 1.clavines,2.
lysergic acid amides (paspalic acid amides), and 3.
peptides (sometimes designated ergopeptides or
ergopeptines).
30.
31. Pharmacological properties
In general, the effects of all the ergot alkaloids appear to results
from their actions as partial agonists or antagonists at adrenergic,
dopaminergic, and tryptaminergic receptors. All of the natural
alkaloids of ergot significantly increase the motor activity of the
uterus. After small doses contractions are increased in force or
frequency, or both, but are followed by a normal degree of
relaxation. As the dose is increased, contractions become more
forceful and prolonged,so used after abortion to control bleeding
and maintain uterine contraction.
Ergot derivatives were first found to be effective anti-migraine and
used as therapeutic agents for the acute relief of moderate or severe
migraine.
32. Vinca alkaloids
Vinca alkaloids derived from Catharanthus roseus
(Apocynaceae).
They are well-known clinical cytotoxic drugs inhibiting
the ability of cancer cells to divide.
It include vinblastine, vincristine, vindesine, and
vinorelbine
Vinca alkaloids such as vinblastine, vinorelbine,
vindesine, and vincristine are used in the treatment of
lymphomas, acute lymphocytic leukemia (ALL), and solid
tumors.
The mechanism of action of vinca alkaloids is to arrest dividing
cells in metaphase by binding tubulin and preventing its
polymerization into microtubules.microtubles after polymerization
cause cell division.
34. Vinca alkaloids are now
produced synthetically and used as drugs in cancer
therapy and as immunosuppressive drugs.
Vinca alkaloids are chemically indole
alkaloids and are known to possess anti-cancer,
anti-hypertensive and anti-diabetic roles.
40. Biosynthesis of Quinine
A survey of literature reveals that the intrinsic details of the
biosynthetic pathways are lacking; however, an assumed
biogenetic process essentially involving the following steps:
1. L-Tryptophan and secologanin yields strictosidine, which
upon hydrolysis and decarboxylation produces coryantheal.
2. Coryantheal undergoes intramolecular changes, first-by
cleavage of C-N bond (via iminium), and secondly-by formation
of an altogether new C-N bond (again via iminium). This gives
rise to an intermediate.
3. The resulting intermediate undergoes further intramolecular
changes to yield cinchoninone having a quinoline nucleus.
4. Cinchoninone in the presence of NADPH* reduces the
carbony function and generates quinine:
43. Biosynthesis of Yohimbine, Reserpine
Dehydogeissoschizine (keto-form) undergoes isomerization by means of
the nucleophilic attack on to carbonyl through a conjugated system, which
subsequently forms an onium ion that upon reduction produces yohimbine as
shown below:
Onium ion
Reserpine
Tryptophan
+
secologanin
44. Reserpine and deserpidine are essentially the trimethoxybenzoyl esters of yohimbine-type
alkaloids; whereas, rescinnamine is a trimethoxycinnamoyl ester. Interestingly,
both reserpine and rescinnamine contain an additional methoxyl moiety present
strategically on the indole ring system at C-11, which is accomplished by virtue of
hydroxylation and methylation at a late stage along the pathway. A predominant and
characteristic feature of these alkaloids is that they exhibit the opposite stereochemistry at
C-3 to yohimbine and strictosidine as depicted below:
45. Biosynthesis of Ergotamine
The various steps involved in the biosynthesis of ergotamine are as enumerated below:
1. Three amino acids, viz., L-alanine, L-phenylalanine, and L-proline in the presence of ATP
and enzyme SH; or D-(+)-lysergic acid in the presence of ATP and enzyme SH undergo two
steps: first-activation via AMP esters, and secondly-attachment to the respective enzymes,
thereby giving rise to an intermediate. It is worthwhile to observe that the enzyme is
comprised of two subunits that essentially bind the substrates as indicated in the
biosynthetic pathway given below.
2. The comparatively more complex structures comprising of the peptide fragments, such
as:ergotamine are eventually formed by sequential addition of amino acid residues to
the thioesterbound lysergic acid, yielding a linear lysergyl-tripeptide covalently attached to
the enzyme complex.
3. The resulting complex undergoes lactam formation followed by release from enzyme. In
other words, the cyclized tripetide residue is rationalized instantly by the formation of a
lactam (amide) that releases ultimately the product from the enzyme.
4. This resulting product first affords hydroxylation then followed by generation of a
hemeketallike linkage to give rise to the formation of ergotamine.
All these aforesaid steps (1) through (4) have been duly depicted in the following
biosynthetic pathway.
46.
47. Biosynthesise of vinca alkaloids
(iv) Vinblastine: The nucleophilie vindoline, C-5 of
the indole nucleous is being activated adequately
by the OMe at C-6, besides the N-atom of the
indole moiety. The resulting adduct is
subsequently reduced in the dihydropyridinium
ring by the NADH-dependent 1, 4-addition, giving
the substrate for hydroxylation. Its ultimate
reduction gives rise to vinblastine.
(v) Vincristine: It is the oxidized product of
vinblastine whereby the inherent N-formyl group
on the indoline fragment is transformed.
50. Biosynthesis of Ephedrine Alkaloids
Interestingly, phenylalanine and ephedrine not only have the same
carbon and nitrogen atoms but also have the same arrangement of
C and N-atoms i.e., the skeleton of atoms. Noticeably, L-
phenylalanine is a precursor, possessing only seven carbons, a
C6C1 fragment, gets actually incorporated. It has been observed that
phenylalanine undergoes metabolism, probably via cinnamic acid to
benzoic acid; and this perhaps in the form of its coenzyme–A ester,
which is acylated with pyruvic acid and undergoes decarboxylation
during the addition as shown below.
A thiamine PP-mediated mechanism is put forward for the
formation of the diketone, and a transamination reaction shall give
rise to cathinone. Further reduction of the carbonyl moiety from
either face yields the
diastereomeric norephedrine or norpseudoephedrine (Cathine).
Ultimately,
N-methylation would give rise to ephedrine or pseudoephedrine.