This document discusses serotonin receptors and their agonists and antagonists. It begins by describing the sources and chemistry of serotonin in the body. It then details the seven main families of serotonin receptors, their locations and functions. The document outlines various pathophysiological roles of serotonin. Finally, it examines several classes of drugs that act as agonists or antagonists at serotonin receptors, describing their mechanisms, indications, and side effects.

1. Dr Ankita Jire
JR
Dept of pharmacology
GMC Nagpur
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2.  Introduction
 Sources & Chemistry
 Synthesis
 Serotonin receptors
 Pharmacological actions of serotonin
 Pathophysiological roles
 Serotonin receptors:Agonists
 Serotonin receptors:Antagonists
 Summary
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3. Serotonin or 5-Hydroxytryptamine (5-HT)
 Biogenic monoamine
 Identified as neurotransmitter in central nervous
system (CNS) & also have prominent peripheral
actions
 Serotonin is found in
GIT
Platelets
CNS
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4.  Present in vertebrates, tunicates, molluscs,
arthropods, coelenterates, fruits & nuts
 Component of venoms of common stinging
nettle, wasps & scorpions.
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5.  5-HT [3-(β-aminoethyl)-5-hydroxyindole]
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7.  Hydroxylation at C5 by tryptophan hydroxylase-1
is rate-limiting step
 5-Hydroxyindole Acetic Acid(5-HIAA) formation
accounts for nearly 100% of metabolism of 5-HT in
brain
 5-Hydroxyindole Acetic Acid (5-HIAA) from brain
& peripheral sites of 5-HT storage & metabolism is
excreted in urine
 Larger amounts are excreted by patients with
malignant carcinoid
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8.  In 1957, Gaddum and Picarelli
 M receptors -located on parasympathetic nerve
endings, controlling release of acetylcholine
 D receptors -located on smooth muscle
5-HT receptor
M receptors
D receptos
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9.  The current classification scheme (Hoyer et al.,
1994) includes seven subfamilies of 5-HT
receptors
5HT receptors
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT2
5-HT2A
5-HT2B
5-HT2C5-HT3
5-HT4
5-HT5
5-HT6
5-HT712/24/2016 9Serotonin receptors: Agonists & antagonists

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11.  Five members
 Preferentially couple to G protein & inhibit
adenylyl cyclase
 5-HT1A, 5-HT1B & 5-HT1D receptor subtypes
activate K+ & inhibit Ca2+ channels
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13. Receptor 5-HT1A 5-HT1D/1B
Location Raphe nuclei of the
brainstem
Substantia nigra & basal
ganglia
Function Neuronal inhibition
Behavioural effects:
sleep, feeding, thermo-
regulation, anxiety
Contraction
CSF production
Neuronal excitation
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14.  3 subtypes
 Couple to G protein→activate phospholipase C
function through Inositol triphosphate /
Diacylglycerol
 5-HT2A inhibits K+ channels
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15. Receptor 5HT2A 5HT2B 5HT2C
Location Vascular & visceral
smooth muscles,
platelets,prefrontal
cortex
Gastric
fundus
Choroid
plexus,
hypothalamus
Function Neuronal excitation,
Smooth muscle
contraction,
Platelet aggregation,
Vasoconstriction
Contraction CSF
production,
feeding
behaviour &
mood
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16.  Ionotropic receptor, belonging to nicotinic-
acetylcholine superfamily of receptors
Location -Parasympathetic
terminals in GI tract,
including vagal &
splanchnic afferents
-CNS
Solitary tract nucleus
& in area postrema
Function Emesis
Neuronal excitation
Behavioural effects:
anxiety
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17.  Couple to G proteins activate adenylyl
cyclase increase in intracellular cyclic AMP
Location -GIT
neurons of myenteric plexus & on smooth muscle
& secretory cells
-CNS
superior & inferior colliculi
Hippocampus
Function Evoke intestinal secretion & peristaltic reflex
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18.  Closely related to 5-HT4 receptor
 Mainly located in specific brain areas but
their functional role is not known
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20. 1.CARDIOVASCULAR SYSTEM
A) Blood Pressure
i.Early sharp fall-due to coronary
chemoreflex (Bezold Jarisch Reflex)
ii.Brief rise - due to vasoconstriction &
increased cardiac output
iii. Prolonged Fall-due to dilatation of blood
vessels
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21. FALL
FALL
RISE
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22. B) Effects on Blood vessels and Hemostasis
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23. C) Heart:
+ve Inotropic, +ve Chronotropic
2. Visceral smooth muscle
GIT- ↑ peristalsis &↑ secretion
Bronchi- Bronchoconstriction
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24. 3. Glands
Inhibits gastric secretion (acid & pepsin) but ↑
mucus production ulcer protective property
4.Nerve endings
Activation of afferent nerve endings- tingling &
pricking sensation, pain
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25. 5.Respiration
Brief stimulation of respiration & hyperventilation
Large doses can cause transient apnea (coronary
chemoreflex)
6.Platelets (5-HT 2A receptor)
Causes changes in shape of platelets & is a weak
aggregator
7.CNS
Direct injection in brain causes sleepiness, change
in body temperature, hunger & behavioural
effects
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26.  Neurotransmitter
Involved in sleep, temperature regulation, thought,
cognitive function, behaviour, mood, appetite, vomiting &
pain perception
 Precursor of melatonin in pineal gland
Regulates biological clock & maintain circadian rhythm
 Neuro-endocrine function
Regulate hypothalamic neurons that control release of
anterior pituitary hormones
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27.  Nausea & vomiting
Evoked by cytotoxic drugs/radiotherapy is mediated by
release of 5-HT
 Migraine
Initiates vasoconstrictor phase of migraine & participates
in neurogenic inflammation of cranial blood vessels
 Haemostasis
Causes platelet aggregation & clot formation at site of
injury to blood vessel & also promotes retraction of
injured vessel
 Raynaud’s phenomenon
5-HT release from platelets may trigger acute
vasospastic episodes of larger arteries
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28.  Hypertension
↑ responsiveness to 5-HT & ↓ uptake & clearance by
platelets seen in hypertensives
 Intestinal motility
Enterochromaffin cells & 5-HT containing neurons
regulate peristalsis & local reflexes in gut (activated
by intestinal distension)
 Carcinoid tumours
Produce massive amounts of 5-HT leading to bowel
hypermotility & bronchoconstriction
-Pellagra due to diversion of tryptophan for
synthesizing 5-HT
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30. 1.Triptans
 Indole derivatives
 Selective 5-HT1D/1B agonists
Ex.Sumatriptan, Eletriptan, Frovatriptan ,Naratriptan,
Zolmitriptan, Rizatriptan, Almotriptan
 Mechanism of action
-5-HT1D/1B receptor mediated constriction of dilated
cranial blood vessels, especially arterio-venous shunts in
carotid artery
-Dilatation of these shunt vessels during migraine
attack is believed to divert blood flow away from
brain parenchyma
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31.  Indication
Treatment of acute attacks of moderate to severe
migraine not responding to analgesics
Sumatript
an
Frovatript
an
Rizatripta
n
Naratripta
n
Zolmitript
an
Oral
bioavail-
Ability(%)
15 25 45 70 40
T
max(Hours)
1.5-2 2-4 1-1.5 2-3 1.5-2
T ½(Hours) 2 26 2-3 6 2-3
Oral
dose(mg)
50-100 2.5 5-10 2.5 2.5
Max dose
(mg/day)
200 7.5 30 5 10
Comparative features of triptans
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32. Side effects
 Tightness in head & chest, paresthesias in limbs,
dizziness, weakness
 Bradycardia, coronary vasospasm & risk of
myocardial infarction
Contraindications
Ischaemic heart disease,
hypertension, epilepsy
Sumatriptan & Ergotamine should not be administered
within 24 hours of each other12/24/2016 32Serotonin receptors: Agonists & antagonists

33.  Donitriptan
Fewer side effects than sumatriptan but same
cardiovascular side effects
Trexima (oral tablet)
• Combination of sumatriptan succinate & naproxen
sodium
• FDA approval-T/t of acute migrain
• Designed to provide faster relief & lesser relapse
rate
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34. 2. selective 5-HT4 agonist
 Prokinetic drugs- increases gastrointestinal motility
Ex.Metoclopramide,Cisapride,Mosapride,Renzapride,
Prucalopride
5-HT4 receptor activation on primary afferent neurones
(PAN) of ENS via excitatory interneurones
Enhance ACh release from myenteric motor neurones
 Indication
-Gastroesophageal reflux disease
-Gastroparesis
-Refractory severe chronic constipation
Side effect
Blocks delayed rectifying K+ channels in heart—prolongs Q-
Tc interval & predisposes to torsades de pointes/ventricular
fibrillation
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35. 3. Azapirones
 Selective partial agonists of 5-HT1A receptors in
brain
Ex.Buspirone, gepirone & ipsapirone
 Reduces activity of dorsal raphe serotonergic
neurons
 Mimics antianxiety properties of benzodiazepines
but does not interact with GABAA receptors
 Indication
Anxiety disorders
Side effects
-Dizziness, nausea,headache, light-headedness
-Rise in BP in patients on MAO inhibitors
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36. 4. Lysergic acid
diethyl amide
(LSD)
5. 8-Hydroxy(2
N,N-
Dipropylamino)-
Tetraline
(8-OH-DPAT)
6. Lorcaserin
Receptors Nonselective 5-HT
agonist 5-HT1A,
5-HT2A/2C, 5-HT5-7
5-HT1A selective
receptor agonist
Selective 5-
HT2C agonist
Action Potent hallucinogen Anti-depressant,
anti-anxiety
Anti-Obesity
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38. 1. Selective 5-HT3 antagonists
 Ex-Ondansetron, Granisetron, Ramosetron &
Palonosetron,Alosetron
 Blocks depolarizing action of 5-HT exerted through
5-HT3 receptors on vagal afferents in g.i.t. as well
as in Nucleus Tractus Solitarius & Chemoreceptor
Trigger Zone
 Indication
-Nausea & vomiting following administration of highly
emetic anticancer drugs & radiotherapy
-Postoperative nausea
-Hyperemesis of pregnancy
-Irritable bowel syndrome
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39. Drug Chemical
nature
Receptor
interactions
T1/2 (hour) Dose (iv)
Ondansetron Carbazole
derivative
5-HT3
antagonist
3.9 0.15 mg/kg
Granisetron Indazole 5-HT3
antagonist
9-11.6 10 μg/kg
Dolasetron Indole
moiety
5-HT3
antagonist
7-9 1.8 mg/kg
Palonosetron Isoquinoline 5-HT3
antagonist:
highest
affinity
40 0.25 mg
Side effects
-Constipation or diarrhea, headache & lightheadedness
-Hypotension, bradycardia, chest pain, allergic reactions
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40. 2. 5-HT2 receptor antagonists
Ex. Trazodone & nefazodone
 Primary metabolite m-chlorphenylpiperazine (m-cpp) is
potent 5-HT2 antagonist
-α Adrenergic antagonist
 Indication
Major depression, Anxiety
 Side effects
Hepatotoxicity,sedation,postural hypotension,priapism
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41. 3.Cyproheptadine
 Primarily blocks 5-HT2A receptors
 Additional H1 antihistaminic, anticholinergic &
sedative properties
 Indication
-Intestinal manifestations of carcinoid &
postgastrectomy dumping syndromes
-migraine prophylaxis
Side effects
Drowsiness, dry mouth, confusion, ataxia, weight gain
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42. 4. Methysergide
 Congener of methylergonovine
 Potent 5-HT2A/2C antagonist
 Acts on 5-HT1 receptors also
 Indication
Migraine prophylaxis, carcinoid & postgastrectomy
dumping syndrome
Side effects
Abdominal, pulmonary & endocardial fibrosis
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43. 5.Ketanserin
 Selective 5-HT2 receptor antagonist
(5HT2A>5HT2C)
Ritanserin (more 5HT2A agonist)
 Additional weak α1, H1 & dopaminergic blocking
activities
 Antagonize 5-HT induced vasoconstriction, platelet
aggregation & contraction of airway smooth muscle
 Indication
Raynaud’s disease
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44. 6. Clozapine
 Inverse agonist at cerebral 5-HT2A/2C receptors
 Indication
Resistant cases of schizophrenia
7. Risperidone,Olanzapine & Quetiapine
 Combined 5-HT2A + dopamine D2 antagonist
 Indication
Schizophrenia
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45. 1.Synthesis inhibitor
P-Chlorophenylalanine (PCPA) selectively inhibits
tryptophan hydroxylase & reduces 5-HT level in
tissues
2. Uptake inhibitor
a)Selective serotonin reuptake inhibitors (SSRI)
b) Serotonin and noradrenaline reuptake inhibitors
(SNRIs)
c)Tricyclic antidepressants
Inhibit monoamine reuptake & interact with
muscarinic, α adrenergic, H1, 5-HT1, 5-HT2 receptors12/24/2016 45Serotonin receptors: Agonists & antagonists

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47. Drug Bioavail
ability
(%)
Plasma
T1/2
(Hours)
Active
metabolite
T1/2
(Hours)
Vd
(L/Kg)
Protein
binding(%)
Citalopram 80 33-38 - 15 80
Escitalopram 80 27-32 - 12-15 80
Fluoxetin 70 48-72 180 12-97 95
Fluvoxamine 90 14-18 14-16 25 80
Paroxetin 50 20-23 - 28-31 94
Sertraline 45 22-27 62-104 20 98
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48.  Indication
Depression, Obsessive- compulsive disorders, panic
disorder, premenstrual dysphoric disorder ,
posttaumatic stress disorder, Generalized anxiety
disorder,
 Side Effects
Insomnia, increased anxiety, irritability &
decreased libido,diarrhoea
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49.  Monoamine Oxidase Inhibitors(MAOI) enhance
effects of SSRIs due to inhibition of serotonin
metabolism
 Synergistic ↑in extracellular brain serotonin
serotonin syndrome
 Symptoms
Hyperthermia, muscle rigidity, myoclonus, tremors,
autonomic instability, confusion & irritability
coma & death
 Treatment
Stop all serotonergic drugs
Nonselective serotonin antagonists12/24/2016 49Serotonin receptors: Agonists & antagonists

50.  Inhibits uptake of both NA & 5-HT
 Ex. Venlafaxine, Duloxetine
 Indication
Depression, anxiety
 Side effects
Nausea, sweating, anxiety, dizziness, impotence
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51. 3.Storage inhibitor
 Reserpine
Blocks 5-HT & NA uptake into storage vesicles by
inhibiting VMAT-2 depletion of all monoamines
 Indication
Hypertension
Side effects
Sedation, mental depression,suicidal tendency,
extrapyramidal symptoms
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52. 4.Degradation inhibitor
Nonselective Monoamine Oxidase Inhibitors
(tranylcypromine) & Selective MAO-A inhibitor
(chlorgyline) ↑5-HT content by preventing its
degradation
5. Neuronal degeneration
5, 6 dihydroxytryptamine selectively destroys 5-HT
neurones
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53. 6. Noradrenergic & specific serotonergic antidepressant
(NaSSA) Mirtazapine
 Blocks α2 auto-receptors (on NA neurones) & hetero-receptors (on
5-HT neurones) enhancing both NA & 5-HT release
 Augmented NA further increases firing of serotonergic raphe
neurones via α1 receptors
 Selective enhancement of antidepressive 5-HT1 receptor action is
achieved by concurrent blockade of 5-HT2 & 5-HT3 receptors which
are responsible for some adverse effects of high serotonergic tone
 Indication
Mild & severe depression with insomniaSide effects
Increased appetite & weight gain
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55. Recept
or
Location Main function Signalling
system
Significant drugs
Agonists Antagonists
5-HT1A CNS(Raphe
nuclei of
brain stem)
Neuronal
inhibition
Behavioural
effects: sleep,
feeding, thermo-
regulation,
anxiety
G protein
(Gi/Go)
↓ cAMP (may
modulate
Ca2+
channels)
Buspirone
(partial
agonist)
Ergotamine
5-HT1B CNS
(Subiculum)
vascular
smooth
muscle
Presynaptic
inhibition
Behavioural
effects
Pulmonary
vasoconstriction
Triptans
5-HT1D CNS(Cranial
blood
vessels)
Cerebral
vasoconstriction
Triptans Ergotamine
(PA)
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56. Receptor Location Main function Signalling
system
Significant drugs
Agonists Antagonists
5-HT2A CNS, PNS,
smooth
muscle,
platelets
Neuronal excitation
Behavioural effects
Smooth muscle
contraction (gut,
bronchi, etc.)
Platelet
aggregation,
Vasoconstriction/va
sodilatation
G protein
(Gq/G11)
↑ IP3,
Ca2+
LSD,α
methyl
5HT
Ketanserin
Ritanserin
Cyproheptadine
Methysergide
5-HT2B Gastric
fundus
Contraction LSD,α
methyl
5HT
5-HT2C CNS
(Choroid
plexus,hypo
thalamus)
CSF production
Neuronal excitation
LSD,α
methyl
5HT
Methysergide
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57. Receptor Location Main function Signalling
system
Significant drugs
Agonists Antagonists
5-HT3 PNS, CNS Neuronal excitation
Emesis
Behavioural effects:
anxiety
Ligand-
gated
cation
channel
2-methyl
5HT
Dolesatron
Granisetron
Ondansetron
Palonosetron
Tropisetron
5-HT4 (GI tract),
CNS
Neuronal excitation
GI motility
G protein
↑cAMP
Metoclo-
Pramide,
cisapride
GR-113808
5-HT5 CNS Modulation of
exploratory
behaviour
As above - -
5-HT6 CNS,
leukocytes
Learning & memory? As above - -
5-HT7 CNS, GI
tract, blood
vessels
Thermoregulation?
Circadian rhythm?
As above - -
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58.  The pharmacological basis of therapeutics - Goodman and
gilman (12th edition)
 Basic And Clinical Pharmacology(Katzung)12th edition
 General pharmacology-Basic concepts(HL Sharma & KK
Sharma)2nd edition
 Subtypes of receptors for serotonin:Annual review of
pharmacology & toxicology 1990
 Neurotransmitters
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