5 HT in Pharmacology &

Therapeutics

Dr Arif Hashmi JR II
Protein receptors that mediate the effect
of 5HT have existed in the membrane of a
variety of cell types of animals for millions
of years, their ancestry being as old as or
older than some of that of adrenoreceptors
and receptors for some peptides.
During such a long period there has been ample

opportunity for mutations and as a consequent a

multitude of different but related receptors today

form the 5 HT family, the largest known

neurotransmitter family
As long ago as 1868 it was known that the
blood contained a vasoconstrictive
substance
In Italy, Erspamer had, since the late 1930s,
been investigating a constituent of gastric and
enteric mucosa of mammals, and salivary
glands of octopus

He had named the compound enteramine and

this substance was finally demonstrated also to
be 5-HT
Irvine Page Arda Green and Maurice
Rapport, isolated and characterised this
substance, and named it for its

vasoconstrictor properties – Serotonin

Gaddum demonstrated the presence of
this newly isolated chemical in the brain

He also demonstrated that the action of

5HT in the gut was antagonised by
LSD, a hallucinogenic substance that
had just been synthesized back then
 Measuring 5HT – Early attempts

 Bioassay using an isolated oestrus uterus

– Amin (1954)

 Rat stomach strip – John Vane (1957)

 Spectophotoflourimeter – Robert Bowman

 HPLC
 Synthesis & Metabolism of 5HT

 5-HT synthesised from tryptophan

 Sequence of steps -
hydroxylation & decarboxylation
 Receptor Identification & Naming

The first definitive identification of 5-HT

receptor subtypes was by Gaddum & Picarelli
(1957)
Gaddum’s classification was the D- and M-

receptor, named because of the sensitivity of

the receptor subtypes to dibenzyline and

morphine as blockers
5HT Receptor subtypes and their
Ligands
The 5-HT1 receptor class is comprised of

five receptor subtypes - 5-HT1A, 5-HT1B, 5-

HT1D, 5-ht1E and 5-ht1F

 5-HT1A receptors

5-HT1A receptors are present widely in the

CNS, especially raphe nucleus
Implicated in -
 Neuro-endocrine regulation of ACTH
but not Prolactin secretion
 Anxiety, 5HT 1A KO mice demonstrate

increased anxiety
 Hyperphagia – pre-synaptic 5HT 1A
autoreceptor activation
Peculiar Lab response -
 Spontaneous tail-flick response attributed
to post-synaptic 5HT1A receptor activation
 5-HT1B receptors

Expressed in the CNS, basal ganglia,

striatum and frontal cortex and are
thought to serve as terminal
autoreceptors
also found in Cerebral arteries and other
vascular tissues
Interest in 5-HT1B receptor agonists has been

enhanced by the antimigraine properties of

Sumatriptan, a non-selective 5HT 1B/1D

agonist
Donitriptan - mixed activity at both 5-HT1D

and 5-HT1B receptors, displays uniquely high

selectivity towards cranial versus peripheral

tissues, thereby leading to drug candidate
with minimal cardiovascular effects
It has completes Phase I trial or migraine
and is currently in Phase II
The putative 5-HT1B receptor agonist,

anpirtoline, has analgesic and

antidepressant-like properties in rodents

5-HT1B receptor KO mice were reported

to be both highly aggressive and have an

increased preference for alcohol
 5-HT1D receptors

The 5HT 1D receptor possesses 63%

overall structural homology with the 5HT 1B

receptor. Its level of expression is very

low compared with 5HT 1B receptors

- dorsal raphe nucleus & human heart

 5-ht1E receptors

The putative 5-ht1E receptor was first

identified in binding studies in homogenates

of humanfrontal cortex, but it was not
possible to readily determine its overall
distribution and pharmacology
 5-ht1F receptors

The 5-ht1F receptor consists of a 366-amino

acid protein, negatively linked to adenylyl

cyclase in recombinant cell systems. This
receptor is most closely related to the 5-ht1E

receptor with >70% sequence homology

The 5-HT2 receptor class is comprised of
the 5-HT2A, 5-HT2B and 5-HT2C receptor

subtypes

couple preferentially to Gq/11 to increase

the hydrolysis of inositol phosphates and
elevate cytosolic Ca2+
 5-HT2A receptors

distributed in the CNS, serotonergic terminal

areas

high densities of 5-HT2A receptors are found

in prefrontal, parietal, and somatosensory

cortex, claustrum, and in platelets
5-HT2A receptors in the GI tract are thought

to correspond to the D subtype of 5-HT

receptor originally described by Gaddum
and Picarelli
5-HT2A receptors mediate contractile

responses in a series of vascular smooth

muscle preparations
Platelet aggregation and increased
capillary permeability following exposure
to 5-HT have been attributed to 5-HT2A

receptor-mediated functions
 5-HT2B receptors

originally were described in stomach fundus

5-HT2B receptor are also seen in cerebellum,

hypothalamus and amygdala

This sub-type has been implicated in -
 Hyperphagia
 Anxiolysis
 Endothelium-dependent relaxation in
vein
 Small intestine smooth muscle
contraction
 5HT2C receptors

Due to lack of selective ligands, current

knowledge is limited

receptor has been implicated in feeding

behavior and susceptibility to seizure
 The 5-HT3 receptor class: an
intrinsic ligand-gated channel

5-HT3 receptors are found on neurones, of

both central and peripheral origin(GI tract,
including vagal and splanchnic afferents),
area postrema
trigger rapid depolarisation due to a transient
inward current, subsequent to the opening of
nonselective cation channels (Na+, Ca2+
influx, K+ efflux).
 5-HT4 Receptor

Widely distributed throughout the body

- CNS
- GI tract 5-HT4 receptors are located on
neurons of the myenteric plexus and on
smooth muscle and secretory cells.
Evoke secretion in the alimentary tract
facilitate the peristaltic reflex

Couple to Gs to activate adenylyl cyclase,

leading to a rise in intracellular levels of
cyclic AMP (cAMP) - as prokinetic
benzamides in gastrointestinal disorders
 5-ht5 receptors
No evidence has been obtained to
confirm that the recombinant 5-ht5
receptor is expressed in an endogenous
setting.
Two subtypes of the 5-ht5 receptor (5-
ht5A and 5-ht5B)
 5-ht6 Receptors

- highly expressed in limbic and extrapyramidal

brain areas
- Atypical anti-psychotics
 5-HT7 receptor

- extensive vascular distribution

- responsible for the prominent persistent
vasodilator response to 5-HT in
anaesthetised animals
- also expressed in nonvascular smooth
muscle and the CNS.
Atypical anti-psychotics, e.g. clozapine
have high affinity for the 5-HT7 receptor
Down-regulation occurs after chronic anti-
depressant use
 5-HT in Therapeutics

1. Migraine
2. Anti-emetic
3. Anxiolytic
4. Schizophrenia
5. Depression
 Migraine

1. Triptans – 5-HT1 agonist

2. Ergot derivatives
Triptans are indole derivatives, with
substituents on the 3 and 5 positions
Sumatriptan, Zolmitriptan, Naratriptan,
Rizatriptan

Sumatriptan is an example of planned

drug discovery
interact potently with 5-HT1D and 5-HT1B
receptors and have a low or no affinity for
other subtypes of 5-HT receptors.
Two hypotheses have been proposed
explaining the causation of Migraine

1. Opening of AV anastomoses around

the carotid

2. Release of pro-inflammatory neuro-

peptides from thr axonal terminals
Triptans MOA can explain both these
hypotheses -
1. causing vasoconstriction
2. pre-synaptic auto-receptor preventing
release of neuropeptides
PK parameters -
1. oral absorption ranges from 14 –
70%
2. peak plasma concentrations are
reached in 1-3 hrs
3. average half life in plasma is 1-
2.5 hrs, maximum being for
Naratriptan -6 hrs
4. protein binding ranges from 14-
30%
5. metabolism – oxidative
deamination
6. excretion – urinary
Adverse Effects -
 Cardiac
 Orally administered triptans can cause
paresthesias; asthenia and fatigue;
flushing; feelings of pressure, tightness, or
pain in the chest, neck, and jaw;
drowsiness; dizziness; nausea; and
sweating
 On inj mild pain, stinging, or burning
Contraindications -
1)h/o vessel disease
2)patients with uncontrolled hypertension
3) Naratriptan c/i severe renal or hepatic
impairment
4) Sumatriptan, rizatriptan, and
zolmitriptan c/i with MAOI
treatment of acute attacks of Migraine


and not intended for prophylactic use.

 taken at the earliest possible

Parenteral administration if vomiting



Cumulative dose has to be within



defined limits
not be used concurrently with Ergot


derivatives and MAOI

 Ergot and its derivatives

An age old drug

Its abortifacient effect has been known
for ages.

Consumption of bread contaminated

with the fungus leads to dramatic effects
– hallucinations, delusions,
posturing. St. Anthony's fire, Salem
witch trials
Numerous semisynthetic derivatives of
the ergot alkaloids have been prepared
by catalytic hydrogenation of the natural
alkaloids, e.g., dihydroergotamine.
Other products of this series include
lysergic acid diethylamide (LSD), a potent
hallucinogenic drug, and methysergide,
a serotonin antagonist.
Adverse effects assoc. with Ergot use
1. Cardiac side effects
2. Prolonged vasospasm, gangrene
3. Abortifacient
4. Nausea & Vomiting
5. Leg cramps, numbness, localized
edema, itching
5-HT-Receptor Antagonists
Ketanserin
 potently blocks 5-HT2A , >5-HT2C

 no significant effect on 5-HT3, 5-HT4,

5-HT1-receptor family
 high affinity for ά adrenergic receptors
and histamine H1 receptors
lowers blood pressure causing a reduction
comparable β adrenergic-receptor
antagonists or diuretics
Reduces the tone of both capacitance and
resistance vessels
effect relates to blockade of α1 adrenergic
receptors, not its blockade of 5-HT2A
receptors
inhibits 5-HT-induced platelet aggregation,
but it does not greatly reduce the capacity of
other agents to cause aggregation.
 Atypical Antipsychotic Drugs
Clozapine
 5-HT2A/2C-receptor antagonist

 reduced incidence of extrapyramidal side

effects
 greater efficacy for reducing negative
symptoms of schizophrenia
 Clozapine also has a high affinity for subtypes
of dopamine receptors.
Methysergide
 blocks 5-HT2A , 5-HT2C receptors

 inhibits vasoconstrictor and pressor effects

of 5-HT, actions of 5-HT on various types of
extravascular smooth muscle
 although methysergide is an ergot
derivative, it has only weak vasoconstrictor
and oxytocic activity
 used for the prophylactic treatment of migraine
and other vascular headaches
 without benefit when given during an acute
migraine attack the protective effect takes 1 to 2
days to develop and disappears slowly when
treatment is terminated
 might be due to the accumulation of an active
metabolite of methysergide, methylergometrine,
which is more potent than the parent drug
 Side effects of methysergide are usually
mild and transient
 Common side effects include gastro-
intestinal disturbances
 symptoms related to vasospasm-induced
ischemia (numbness and tingling of
extremities, pain in the extremities, and
low back and abdominal pain)
 CNS -psychosis, anxiety, insomnia
 inflammatory fibrosis
 fibrosis regresses after drug
withdrawal
 if methysergide is used
chronically, treatment should be
interrupted for 3 weeks or more
every 6 months
Cyproheptadine
 structure resembles that of the phenothiazine
histamine H1-receptor antagonists it is an
effective H1-receptor antagonist
 prominent 5-HT blocking activity on smooth
muscle by virtue of its binding to 5-HT 2A

receptors.
 weak anticholinergic activity and possesses
mild CNS depressant properties
 effective in controlling skin allergies, pruritus.
 to counteract the sexual side effects of
selective 5-HT-reuptake inhibitors such as
fluoxetine and sertraline
 weight gain and increased growth in children
have been observed and attributed to
impaired regulation of growth-hormone
secretion
References

1. Green R. Neuropharmacology of 5 Hydroxy

Tryptamine. British Journal of Pharmacology (2006)
147, S145–S152

2. Hoyer et al. International Union of Pharmacology

Classification of Receptors for 5-
Hydroxytryptamine. Pharmacological Reviews (1994)
46(2).

3.Brunton et al. Goodman & Gilman's The

Pharmacological Basis of Therapeutics, 11e

4. Katzung et al. Basic & Clinical Pharmacology, 11e