serotonin receptors agonists & antagonists
TRANSCRIPT
05/01/2023Serotonin receptors: Agonists & antagonists
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SEROTONIN RECEPTORS: AGONISTS & ANTAGONISTS
Dr Ankita JireJR
Dept of pharmacologyGMC Nagpur
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OVERVIEW Introduction Sources & Chemistry
Synthesis Serotonin receptors
Pharmacological actions of serotonin Pathophysiological roles
Serotonin receptors:Agonists Serotonin receptors:Antagonists
Summary
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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
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SOURCES Present in vertebrates, tunicates, molluscs, arthropods, coelenterates, fruits & nuts
Component of venoms of common stinging nettle, wasps & scorpions.
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CHEMISTRY 5-HT [3-(β-aminoethyl)-5-hydroxyindole]
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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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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
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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
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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
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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
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5HT2 RECEPTORS 3 subtypes Couple to G protein→activate phospholipase C
function through Inositol triphosphate / Diacylglycerol
5-HT2A inhibits K+ channels
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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
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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
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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
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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
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C) Heart:
+ve Inotropic, +ve Chronotropic
2. Visceral smooth muscle
GIT- ↑ peristalsis &↑ secretion
Bronchi- Bronchoconstriction
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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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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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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
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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
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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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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
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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
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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
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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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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
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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
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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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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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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
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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
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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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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
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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
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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
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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
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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
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Indication
Depression, Obsessive- compulsive disorders, panic disorder, premenstrual dysphoric disorder , posttaumatic stress disorder, Generalized anxiety disorder,
Side EffectsInsomnia, increased anxiety, irritability & decreased libido,diarrhoea
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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
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SNRI Inhibits uptake of both NA & 5-HT
Ex. Venlafaxine, Duloxetine
IndicationDepression, anxiety
Side effectsNausea, sweating, anxiety, dizziness, impotence
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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
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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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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
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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)
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5HT 2 RECEPTORSReceptor
Location Main function Signalling system
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
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Receptor
Location Main function Signalling system
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 - -
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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