serotonin receptors agonists & antagonists

05/01/2023Serotonin receptors: Agonists & antagonists

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SEROTONIN RECEPTORS: AGONISTS & ANTAGONISTS

Dr Ankita JireJR

Dept of pharmacologyGMC Nagpur

05/01/2023Serotonin receptors: Agonists & antagonists 2

OVERVIEW Introduction Sources & Chemistry

Synthesis Serotonin receptors

Pharmacological actions of serotonin Pathophysiological roles

Serotonin receptors:Agonists Serotonin receptors:Antagonists

Summary


INTRODUCTIONSerotonin or 5-Hydroxytryptamine (5-HT)

Biogenic monoamine Identified as neurotransmitter in central

nervous system (CNS) & also have prominent peripheral actions

Serotonin is found in

GITPlatelets

CNS


SOURCES Present in vertebrates, tunicates, molluscs, arthropods, coelenterates, fruits & nuts

Component of venoms of common stinging nettle, wasps & scorpions.


CHEMISTRY 5-HT [3-(β-aminoethyl)-5-hydroxyindole]


SYNTHESISSYNTHESIS


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


HISTORY 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


The current classification scheme (Hoyer et al., 1994) includes seven subfamilies of 5-HT receptors 5HT receptors

5-HT15-HT1A5-HT1B5-HT1D5-HT2

5-HT2A5-HT2B5-HT2C5-HT35-HT45-HT55-HT65-HT7


5 HT1 RECEPTORS Five members Preferentially couple to G protein & inhibit

adenylyl cyclase 5-HT1A, 5-HT1B & 5-HT1D receptor subtypes

activate K+ & inhibit Ca2+ channels


Receptor

5-HT1A 5-HT1D/1B

Location Raphe nuclei of the brainstem

Substantia nigra & basal ganglia

Function Neuronal inhibitionBehavioural effects:

sleep, feeding, thermo-

regulation, anxiety

ContractionCSF productionNeuronal excitation


5HT2 RECEPTORS 3 subtypes Couple to G protein→activate phospholipase C

function through Inositol triphosphate / Diacylglycerol

5-HT2A inhibits K+ channels


Receptor 5HT2A 5HT2B 5HT2CLocation 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


5HT3 RECEPTORS Ionotropic receptor, belonging to nicotinic-

acetylcholine superfamily of receptorsLocation

-Parasympathetic terminals in GI tract, including vagal & splanchnic afferents

-CNSSolitary tract nucleus & in area postrema

Function

EmesisNeuronal excitation Behavioural effects: anxiety


5HT4 RECEPTORS Couple to G proteins activate adenylyl

cyclase increase in intracellular cyclic AMP

Location -GITneurons of myenteric plexus & on smooth muscle & secretory cells

-CNSsuperior & inferior colliculiHippocampus

Function Evoke intestinal secretion & peristaltic reflex


5HT5,5HT6,5HT7

Closely related to 5-HT4 receptor

Mainly located in specific brain areas but their functional role is not known


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PHARMACOLOGICAL ACTIONS1.CARDIOVASCULAR SYSTEM

A) Blood Pressurei.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


FALL

FALL

RISE


B) Effects on Blood vessels and Hemostasis


C) Heart:

+ve Inotropic, +ve Chronotropic

2. Visceral smooth muscle

GIT- ↑ peristalsis &↑ secretion

Bronchi- Bronchoconstriction


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


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


PATHOPHYSIOLOGICAL ROLES Neurotransmitter Involved in sleep, temperature regulation, thought,

cognitive function, behaviour, mood, appetite, vomiting & pain perception

Precursor of melatonin in pineal glandRegulates biological clock & maintain circadian rhythm

Neuro-endocrine functionRegulate hypothalamic neurons that control release of anterior pituitary hormones


Nausea & vomitingEvoked 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


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


5-HT RECEPTOR :AGONISTS


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 migraineattack is believed to divert blood flow away frombrain parenchyma


Indication Treatment of acute attacks of moderate to severe migraine not responding to analgesics

Sumatriptan

Frovatriptan

Rizatriptan

Naratriptan

Zolmitriptan

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


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 other


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


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 effectBlocks delayed rectifying K+ channels in heart—prolongs Q-Tc interval & predisposes to torsades de pointes/ventricular fibrillation


3. Azapirones

Selective partial agonists of 5-HT1A receptors in brainEx.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


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


SEROTONIN RECEPTOR: ANTAGONISTS


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


Drug Chemical nature

Receptor interactio

ns

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


2. 5-HT2 receptor antagonists

Ex. Trazodone & nefazodone

Primary metabolite m-chlorphenylpiperazine (m-cpp) is potent 5-HT2 antagonist-α Adrenergic antagonist

IndicationMajor depression, Anxiety

Side effectsHepatotoxicity,sedation,postural hypotension,priapism


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


4. Methysergide Congener of methylergonovine

Potent 5-HT2A/2C antagonist

Acts on 5-HT1 receptors also

IndicationMigraine prophylaxis, carcinoid & postgastrectomy dumping syndrome

Side effectsAbdominal, pulmonary & endocardial

fibrosis


5.Ketanserin Selective 5-HT2 receptor antagonist

(5HT2A>5HT2C)Ritanserin (more 5HT2A agonist)

Additional weak α1, H1 & dopaminergic blockingactivities

Antagonize 5-HT induced vasoconstriction, platelet aggregation & contraction of airway smooth muscle

IndicationRaynaud’s disease


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

IndicationSchizophrenia


DRUGS AFFECTING 5-HT SYSTEM

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 receptors


SSRI


Drug Bioavailabili

ty(%)

Plasma T1/2

(Hours)

Active metabolit

eT1/2

(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


Indication

Depression, Obsessive- compulsive disorders, panic disorder, premenstrual dysphoric disorder , posttaumatic stress disorder, Generalized anxiety disorder,

Side EffectsInsomnia, increased anxiety, irritability & decreased libido,diarrhoea


SEROTONIN SYNDROME Monoamine Oxidase Inhibitors(MAOI) enhance

effects of SSRIs due to inhibition of serotonin metabolism

Synergistic ↑in extracellular brain serotonin serotonin syndrome

SymptomsHyperthermia, muscle rigidity, myoclonus, tremors, autonomic instability, confusion & irritability coma & death

TreatmentStop all serotonergic drugsNonselective serotonin antagonists


SNRI Inhibits uptake of both NA & 5-HT

Ex. Venlafaxine, Duloxetine

IndicationDepression, anxiety

Side effectsNausea, sweating, anxiety, dizziness, impotence


3.Storage inhibitor

Reserpine

Blocks 5-HT & NA uptake into storage vesicles by inhibiting VMAT-2 depletion of all monoamines

IndicationHypertension

Side effectsSedation, mental depression,suicidal tendency,

extrapyramidal symptoms


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


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

IndicationMild & severe depression with insomnia

Side effectsIncreased appetite & weight gain


5HT1 RECEPTORSReceptor

Location Main function Signalling system

Significant drugs

AgonistsAntagonist

s5-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)


5HT 2 RECEPTORSReceptor


Significant drugs

Agonists Antagonists

5-HT2A CNS, PNS, smooth muscle, platelets

Neuronal excitationBehavioural effectsSmooth muscle contraction (gut, bronchi, etc.)Platelet aggregation, Vasoconstriction/vasodilatation

G protein (Gq/G11)↑ IP3, Ca2+

LSD,α methyl 5HT

KetanserinRitanserinCyproheptadineMethysergide

5-HT2B Gastric fundus

Contraction LSD,α methyl 5HT

5-HT2C CNS (Choroid plexus,hypothalamus)

CSF productionNeuronal excitation

LSD,α methyl 5HT

Methysergide


Receptor


Significant drugs

Agonists

Antagonists

5-HT3 PNS, CNS Neuronal excitation EmesisBehavioural effects: anxiety

Ligand-gated cation channel

2-methyl 5HT

DolesatronGranisetronOndansetronPalonosetronTropisetron

5-HT4 (GI tract), CNS

Neuronal excitationGI 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 - -


References 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

serotonin receptors agonists & antagonists

Education