5-HT Receptor Agonists and Antagonists PDF

5-Hydroxytryptamine Dr Jigneshkumar I. Patel Lecturer, B. K. Mody govt. Pharmacy College, Rajkot  Content:-  Introduction  Distribution, synthesis and metabolism  Types of receptors, agonists and antagonists  Drugs affecting serotonergic neurotransmission  Path...

5-Hydroxytryptamine Dr Jigneshkumar I. Patel Lecturer, B. K. Mody govt. Pharmacy College, Rajkot  Content:-  Introduction  Distribution, synthesis and metabolism  Types of receptors, agonists and antagonists  Drugs affecting serotonergic neurotransmission  Pathophysiology of 5-HT  Role of 5-HT in clinical conditions  Recent advances  GTU questions  Reference  Introduction:-  5-HT is an important neurotransmitter in the brain and periphery and also a local hormone.  The biologically active, low molecular weight, factor originally detected in extracts of gut (enteramine) and in blood serum (serotonin) was eventually identified chemically as a 5-HT.  Play important role as – (1) Neurotransmitter (2) Hormone (3) Autacoid (amine autacoid) Distribution:-  About 90% of total amount present in enterochromaffin cells throughout the GIT  In blood 5-HT is present in high concentration platelets, which accumulate it from the plasma by an active transport system and release it when they aggregate at site of tissue damage.  Broadly in the CNS And in high concentration in localized regions of the midbrain. Biosynthesis and metabolism:-  Principal route of metabolism is Oxidative deamination by MAO  An alternative route is the reduction of the acetaldehyde to an 5-hydroxytryptophol  Classification of receptors:  Gaddam & picarelli (1957) classified 5-HT receptors into  musculotropic (D type) and  neurotropic (M type)  on the basis of their blockadge by Dibenzyline (phenoxybenzamine) and Morphine.  The present system of classification is based on molecular classification is based on molecular characterization and cloning of the receptor cDNA.  All 5-HT receptors are GPCR which function through decreasing (5-HT1) or increasing (5-HT4, 6, 7) cAMP production or by generating IP3/DAG (5-HT2) as secondary messenger  5-HT3 is ligand gated cation (Na+, K+) channel. Classification of receptors: (1) 5-HT1 Receptors: This family consists of 5 members. 5-HT1A, 1B, 1D, 1E, 1F All subtypes of 5-HT1 receptor couple with Gi/Go protein and inhibit adenylyl cyclase 5-HT1A receptor is found in the raphe nuclei of the brainstem, where it functions as an inhibitory, somatodendritic autoreceptor on cell bodies of serotonergic neurons. 5-1D expressed in substantia nigra and basal ganglia, regulate the release of dopamine at axonal terminals. 5-HT1D/1B cause Constriction of cranial blood vessels. The antianxiety drug buspirone acts as a partial agonist of 5- HT1A receptor. The antimigraine drug sumatriptan is a selective 5-HT1D/1B agonist.  Classification of receptors: (2) 5-HT2 Receptors: There are 3 subtypes of 5-HT2 receptors – 5-HT2A, 2B, 2C All are coupled to Gq protein → activate phospholipase C and function through generation of IP3/DAG. 5-HT2A is located in the vascular and visceral Smooth muscle, platelets and cerebral neurones especially prefrontal cortex It cause vasoconstriction, intestinal, uterine and bronchial contraction, platelet aggregation and activation of cerebral neurones.  Classification of receptors: (2) 5-HT2 Receptors:  5-HT2B receptors originally were found in stomach fundus, where they are abundant. The expression of 5-HT2B receptors is highly restricted in the CNS.  Contraction of rat gastric fundus is mediated by 5-HT2B receptor  5-HT2C receptor is located on vascular endothelium elicits vasodilatation through EDRF release; Choroid plexus expresses large number of 5-HT2C receptors which may regulate CSF formation.  The 5-HT2C receptor is the only GPCR that is regulated by RNA editing.  This receptor activate the phospholipase A2, promoting the arachidonic acid release.  α-methyl 5-HT is a selective agonist for all 3 subtypes.  Ketanserin is a 5-HT2 antagonist more selective for 5-HT2A.  Classification of receptors: (3) 5-HT3 Receptors: This is the only receptor which function as a ligand-gated ion channel These receptors are located on parasympathetic terminals in the GI tract, including vagal and splanchnic afferents. In the CNS, a high density of receptors is found in the solitary tract nucleus and in the area postrema. 5-HT3 receptors in both the GI tract and the CNS participate in the emetic response, providing a basis for the anti-emetic property of 5-HT3 receptor antagonists. Classification of receptors: 5-HT3 receptors in both the GI tract and the CNS participate in the emetic response, providing a basis for the anti-emetic property of 5-HT3 receptors antagonists. Ondansetron is a selective 5-HT3 antagonist which inhibits vomiting by blocking these receptors in the brainstem as well as in gut wall. 2-Methyl 5-HT is a selective 5-HT3 agonist. Classification of receptors: (4) 5-HT4 Receptors: The 5-HT4 receptor couples to Gs protein, activates adenylyl cyclase 5-HT4 receptors are widely distributed throughout the body, in the CNS found on neurons of superior and inferior colliculi and hippocampus, in GIT located on neurons of mesenteric plexus and on smooth muscle and secretory cells. In GIT, stimulation of this receptor is thought to evoke secretion and to facilitate the peristaltic reflex. Effect of pharmacological manipulation of 5-HT4 receptors on memory and feeding in animal models suggest possible clinical applications in future. Cisapride and renzapride are selective 5-HT4 agonists. Classification of receptors: (5) 5-HT5 Receptors:  This receptor family consists of 2 members- 5-HT5A, and 5-HT5B  5-HT5B receptors is expressed in mouse and rate but not expressed in humans where the coding seqense is interrupted by stop codons.  5-HT5A is distributed in human brain including the cerebral cortex, hippocampus, thalamus, hypothalamus, habenula, cerebellum, and spinal cord. Classification of receptors: (6) 5-HT6 Receptors: High density of receptor was found in the striatum and particularly in ventral striatum. Main role on the memory improvement. Which increase the adenylyl cyclase and leads to the neuronal excitation clozapine (atypical antipsychotic) has high affinity for 5-HT6 (7)5-HT7 Receptors: It is located on GIT, hippocampus, and hypothalamus. Which involved in control of memory, locomotor and exploratory activity, circadian rhythm.  Pharmacological action 1. Platelets:  5-HT2A involved in platelet aggression.  If endothelium is intact , 5-HT release from adherent platelets cause vasodilation, which helps to sustained blood flow.  If it is damaged (eg. Atherosclerosis), 5-HT cause constriction and impairs blood flow.  These effect of platelet-derived 5-HT are important in vascular disease.  Pharmacological action: (2) Cardiovascular system  Serotonin produces positive chronotropic and inotropic effects of varying intensity directly on myocardium and indirect actions mediated by release of norepinephrine from sympathetic nerve terminals.  In vivo such effects are overshadowed by the action of 5-HT on baroreceptor and reflux mechanisms, chemoreceptors and vagal endings in the coronary bed. So inhibition of sympathetic nerve endings leads to bradycardia.  Pharmacological action: (3) GIT 5-HT released from enterochromaffin cells also acts locally to regulate GI function. 5-HT3 receptor promote the release of 5-HT while 5-HT4 inhibit the release of 5-HT 5-HT2A cause contraction of intestinal smooth muscle 5-HT2B cause contraction of stomach fundus smooth muscle  5-HT4 cause contraction of esophagus  Pharmacological action: (3) GIT In the presynaptic ganglion cells 5-HT4 promote the release of Ach while 5-HT1A inhibit the Ach release. In the postsynaptic ganglion cells 5-HT3 cause fast depolarization and 5-HT1 cause slow depolarization Enteric 5-HT triggers peristaltic contraction when released in response to Ach, Sympathetic nerve stimulation, Increase in intraluminal pressure and lowered pH. Pharmacological action: (4) CNS  It excites some neurons and inhibit others; also acts presynaptically to inhibit transmitter release from nerve terminals.  5-HT1A, B increase K+ conductance and cause hyperpolarization of raphe cells  5-HT2A, 2C decrease K+ conductance and cause slow depolarization on the prefrontal cortex and nucleus accumbens  5-HT2A also act on Ca+2-activated membrane currents which enhance the neuronal excitability and potentiates the response to excitatory signals such as glutamate.  5-HT3 reflects direct gating of Na+ and K+ ion channel and cause the fast depolarization in CNS, sympathetic ganglia, primary afferent parasympathetic and sympathetic nerves, and enteric neurons.  5-HT4 coupled to activation of adenylyl cyclase, and elicits a slow neuronal depolarization mediated by a increase in K+ conductance. Pharmacological action: (5). Nerve endings  5-HT stimulates nociceptive (pain-mediating) sensory nerve endings, an effect mediated by 5-HT3 receptor. If injected into skin, it causes pain If given systemically, it elicits a variety of automatic reflexes through stimulation of afferent fibers in the heart and lungs,which complicate the cardiovascular response. 5-HT also inhibit transmitter release from adrenergic neurones in the periphery. Pharmacological action: (6). Glands Inhibit the gastric secretion, but Increase mucus production. It thus has ulcer protective property. Effects on other glandular secretions is not significant. (7). Respiration A brief stimulation of respiration (mostly reflex from bronchial afferents) and hyperventilation are the usual response, but large doses can cause transient apnoea through coronary chemoreflex. Pathophysiological role of 5-HT: (1). Neurotransmitter 5-HT appears to be involved in sleep, temperature regulation, thought, cognitive function, behaviour and mood, appetite, vomiting and pain perception. Some serotonergic neurones are present in intestines also. (2) Precursor of melatonin precursor of melatonin in pineal gland regulate the biological clock and maintain circadian rhythm. (3). Neuroendocrine function  The hypothalamic neurones that control release of anterior pituitary hormones are probably regulated by serotonergic mechanism. Pathophysiological role of 5-HT: (4). Nausea and vomiting Especially that evoked by cytotoxic drugs or radiotherapy is mediated by release of 5-HT and its action on 5-HT3 receptors in the gut, area postrema and nucleus tractus solitarious. (5). Haemostasis Platelets release 5-HT during aggregation at the site of injury to blood vessel. Acting in concert with collagen and other mediators, this 5-HT accelerates platelet aggregation and clot formation. Its contractile action appears to promote retraction of the injured vessel. Both the above actions contribute to haemostasis.  Pathophysiological role of 5- HT: (6). Raynaud’s phenomenon Release of 5-HT from platelets may trigger acute vasospastic episodes of larger arteries involved in Raynaud’s phenomena. Ketanserin has prophylactic value (7). Hypertension Increased responsiveness to 5-HT as well as its reduced uptake and clearance by platelets has been demonstrated in hypertensive patients.  Ketanserin has antihypertensive property. 5-HT has been held responsible for preeclamptic rise in BP.  Pathophysiological role of 5-HT (8). Carcinoid syndrome The carcinoid tumours produce massive quantities of 5-HT.  Bowel hypermotility and bronchoconstriction in carcinoid is due to 5-HT but flushing and hypotension are probably due to other mediators. Pellagra may occur due to diversion of tryptophan for synthesizing 5-HT. (9) Migraine 5-HT is said to initiate the vasoconstrictor phase of migraine and to participate in neurogenic inflammation of the affected blood vessels. Pathophysiological role of 5-HT: (9). Migraine contd...  5-HT receptor agonists: Buspirone It is a partial agonist at 5-HT1A receptors.  It is used in the treatment of anxiety. Ipsapirone and gepirone are newer compounds which take days or weeks to produce their effect on man as compared to benzodiazepines. They do not produce sedation and motor incoordination as seen in benzodiazepines.  They do not produce withdrawal effects like benzodiazepines. Unlike the benzodiazepines it doesn’t interact with GABA A  5-HT receptor agonists: D-Lysergic acid Diethylamide It is non-selective, ergot derivative agonist alters human behaviour, eliciting perception disturbances such as sensory distortion (especially visual) and hallucinations at low dose. It is a nonselective 5-HT agonist activates many subtypes of 5-HT receptors including 5-HT1A on raphe cell bodies, 5-HT2A/2C (probably responsible for the hallucinogenic effect) and 5-HT5-7 in specific brain areas.  It antagonizes 5-HT2A receptors in the ileum  5-HT receptor agonists: 8-OH-DPAT It is 8-OH-(2-N,N dipropylamino)tetraline.  It is a selective 5-HT1A agonist.  It reduces the firing rate of raphe cells by activating 5-HT1A autoreceptors and inhibits neuronal firing in terminal fields by direct interaction with postsynaptic 5- HT1A receptors. Sumatriptan Sumatriptan and other triptans are selective 5-HT1D/1B agonists, constrict cerebral blood vessels and have emerged as the most effective treatment of acute migraine attacks. It is contraindicated in IHD patients because it causes spasm of coronary artery. 5-HT receptor agonists: Cisapride This prokinetic drug which increases gastrointestinal motility is a selective 5- HT4 agonist. Renzapride is still more selective for 5-HT4 receptors. It binds and activates 5-HT4 receptor on myenteric neurons leading to acetylcholine release and contraction of gastric smooth muscle. Tegaserod It is a selective partial agonist on 5-HT4 receptor, is one-fifth as potent as endogenous serotonin and accelerates gastric emptying, colonic filling and colonic transit by stimulating GI smooth muscles. It also blunts the somatic reflex to colonic distension, which may minimize discomfort in IBS  5-HT receptor agonists: 2-methyl-5-HT 2-Methyl-5-hydroxytryptamine is a tryptamine derivative closely related to the neurotransmitter serotonin which acts as a moderately selective full agonist at the 5-HT₃ receptor  5-HT receptor antagonists: Methysergide It is chemically related to ergot alkaloids; antagonizes action of 5-HT on smooth muscles including that of blood vessels, without producing other ergot like effects: does not interact with α adrenergic or dopamine receptors. potent 5-HT2A/2C antagonist with some tissue specific agonistic actions as well; but is nonselective—acts on 5-HT1 receptors It has been used for migraine prophylaxis, carcinoid and postgastrectomy dumping syndrome. Prolonged use has caused abdominal, pulmonary and endocardial fibrosis, because of which it has gone into disrepute.  5-HT receptor antagonists: Cyproheptadine It primarily blocks 5-HT2A receptors and has additional H1 antihistaminic, anticholinergic and sedative properties In allergic conditions, the action of cyproheptadine as a 5-HT receptor antagonist is irrelevant, since 5-HT2A receptors are not involved in human allergic responses. The anti 5-HT activity of cyproheptadine has been utilized in controlling intestinal manifestations of carcinoid and postgastrectomy dumping syndromes as well as in antagonizing priapism/ orgasmic delay caused by 5-HT uptake inhibitors like fluoxetine and trazodone. It increases appetite and has been used in children and poor eaters to promote weight gain.  5-HT receptor antagonists: Ketanserin Selective 5-HT2 receptor antagonist, with negligible action on 5-HT1, 3, 4 Blockade of 5-HT2A is stronger than 5-HT2C blockade. 5-HT induced vasoconstriction, platelet aggregation and contraction of airway smooth muscle are antagonized Additional weak α1, H1 and dopaminergic blocking activities Effective antihypertensive, but α1 adrenergic blockade appears to be causative rather than 5-HT2Ablockade. Trials of Ketanserin in vasospastic conditions have shown symptomatic improvement only in Raynaud’s disease.  5-HT receptor antagonists: Clozapine This atypical antipsychotic is a 5-HT2A/2C blocker. Clozapine may also exert inverse agonist activity at cerebral 5-HT2A/2C receptors which may account for its efficacy in resistant cases of schizophrenia. Reduced incidence of extrapyramidal side effects compared to the classical neuroleptics. Other atypical antipsychotic drugs are risperidone, quetiapine and olanzapine  5-HT receptor antagonists: Ondansetron It is the prototype of the new class of selective 5-HT3 antagonists that have shown remarkable efficacy in controlling nausea and vomiting following administration of highly emetic anticancer drugs and radiotherapy. Other drugs are granisetron and tropisetron.  control cancer chemotherapy/radiotherapy induced vomiting, and later found to be highly effective in PONV  Drugs affecting on serotonergic neurotransmission: 1. Degradation inhibitors MAO inhibitors  Monoamine oxidase is a key enzyme for Serotonin, Dopamine and Norepinephrine inactivation  Used in treatment of Depression (tranylcypromine, phenelzine), Parkinson disease (selegiline) 2. Storage inhibitors. Dextromethorphan, Reserpine  They interfere with ability of synaptic vesicles to store monoamine  Displace Serotonin, Dopamine and nor epinephrine from their storage in presynaptic nerve terminals  Drugs affecting serotonergic neurotransmission: 3. Reuptake inhibitors SNRI(Serotonin Norepinephrine Reuptake inhibitors)  SNRIs mechanism involves blockade of serotonin and nor epinephrine reuptake in a concentration dependent manner  Agents in this class include Venlafaxine and Duloxetine  Effective for the treatment of depression in patients SSRIs (Selective Serotonin Reuptake Inhibitors)  SSRIs block the reuptake of serotonin  Enhance post synaptic neuronal activity  Used to treat depression such as anxiety disorders  Ex: Citalopram, Escitalopram, Fluoxetine, Paroxetine, Sertraline, Vilazodone  Drugs affecting serotonergic neurotransmission: SARIs (Serotonin Antagonist and reuptake inhibitors)  SARIs are class of drugs used as antidepressant, anxiolytics and hypnotics  Inhibits reuptake of serotonin , dopamine and nor epinephrine  Currently marketed SARIs belong to phenyl piperazine class of compounds  Ex: Lorpriprazole, Trazodon, Nefazodone, Mepiprazole TCAs (Tricyclic Antidepressants)  Act by inhibiting reuptake of 5-HT and nor epinephrine from the synaptic cleft by blocking 5-HT and nor epinephrine reuptake transporters.  Increase the post synaptic response  Ex: Imipramine, Desipramine, Trimipramine  Antimigraine drugs 1. Triptans Sumatriptan, Amlotriptan, Frovatriptan, Naratriptan, Rizatriptan, Zolmitriptan Use:- Acute MOA :- 5-HT1B/1D/1F receptor agonist Constriction of large arteries, inhibit trigeminal nerve terminals Side effects:- Coronary vasoconstriction, dysrhythemias Contraindication:- coronary disease  Pathophysiological role of 5-HT: 2. Ergotamine Use:- Acute MOA:- 5-HT1 receptor partial agonist; also affects α adrenoreceptors. Vasoconstrictor. Block trigeminal nerve transmission. Side effects:- Peripheral vasoconstriction, including coronary vessels. Nausea and vomiting. Contracts uterus and may damage fetus. Pathophysiological role of 5-HT:  Advances of 5-HT: 1. Chemotherapy-induced nausea and vomiting (CINV) involving 5-HT3 receptor antagonist  CINV remains poorly controlled in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC); nausea and delayed-phase CINV (24–120 hours after chemotherapy) are the most difficult to control.  HEC include a four-drug regimen (5HT3 RA, neurokinin 1 [NK1] RARA, dexamethasone, and olanzapine).  For some MEC regimens, a three-drug regimen (5HT3 RA, NK1 RA, and dexamethasone) is recommended.  While 5HT3 R ants have dramatically improved CINV in the acute phase (0–24 hours after chemotherapy), their efficacy declines in the delayed phase.  Newer formulations have been developed to extend 5-HT3 receptor antagonist efficacy into the delayed phase.  Granisetron extended-release subcutaneous (GERSC), the most recently approved 5HT3 RA, provides slow, controlled release of therapeutic granisetron concentrations for ≥5 days.  Advances in 5-HT: 2. Novel acute treatment targets in Migraine Novel targeted acute and preventive therapies have emerged including ditans (5-HT 1F receptor agonists), gepants (calcitonin gene-related peptide(CGRP) receptor antagonists) and anti-CGRP monoclonal antibodies (mAbs). Triptans are 5-HT1B/1D receptor agonists with some affinity for the 5-HT 1F receptor subtype and commonly used as acute anti-migraine drugs It cause vasoconstriction due to 5-HT1B receptor, so contraindicated in cardiovascular disease. Therefore, drug pharmacological studies have focused on the 5-HT 1D and 5-HT1F receptors that do not a vasoconstrictive effect. But there is no expected result in trials of 5-HT 1D Therefore, drug discovery programs shifted focus to the 5-HT 1F Subtype. This receptor subtype is located in the trigeminal Ganglion, the trigeminal nucleus caudalis and cephalic blood Vessels, but importantly, activation of this receptor do not Constrict blood vessels  Advances in 5-HT: 2. Novel acute treatment targets in Migraine Contd....  Sumatriptan and naratriptan binds to the 5-HT1F receptor with a high affinity.  Based on these studies, 5-HT1F agonists have been developed and categorized as a new drug class: ditans.  Studies of ditans in preclinical models suggested an involvement in the modulation of dural neurogenic inflammation and the trigeminovascular system, establishing the 5-HT1F receptor as a potential target for migraine treatment  Three compounds exist, LY 344864, LY334370 and lasmiditan  The development of LY334370 was terminated due to hepatic toxicity in animal models  Lasmiditan will likely be approved as second-line treatment if patients failed with triptans or first line anti-migraine treatment in patients with cardiovascular risk References: 1. The Pharmacological Basis of Therapeutics, Goodman and Gillman‘s , 12th edition 2. Pharmacology by H.P. Rang, M.M. Dale, J.M. Ritter, P.K. Moore, 8th edition 3. Essentials of Medical Pharmacology, K.D Tripathi, 7th edition 4. Basic and Clinical Pharmacology by B.G Katzung, 12th edition 5. Do et al. The Journal of Headache and Pain (2019) 20:37 6. https://doi.org/10.1186/s10194-019-0974-3 7. https://doi.org/10.1016/j.ibror.2019.01.001