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Transcript
5-HT receptor The serotonin receptors also known as 5-hydroxytryptamine receptors or 5-HT receptors are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs) found in the central and peripheral nervous systems.[1][2] They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand. The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. The serotonin receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. The serotonin receptors are the target of a variety of pharmaceutical and illicit drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens.[3] Classification With the exception of the 5-HT3 receptor, a ligand-gated ion channel, all other serotonin receptors are G protein-coupled receptors that activate an intracellular second messenger cascade to produce an excitatory or inhibitory response. Families Family Type 5-HT1 Gi/Go-protein coupled. 5-HT2 Gq/G11-protein coupled. 5-HT3 5-HT4 5-HT5 Ligand-gated Na+ and K+ cation channel. Gs-protein coupled. Gi/Go-protein coupled.[4] Mechanism Decreasing cellular levels of cAMP. Increasing cellular levels of IP3 and DAG. Potential Inhibitory Depolarizing plasma membrane. Excitatory Increasing cellular levels of cAMP. Decreasing cellular levels of cAMP. Excitatory Inhibitory Excitatory 5-HT6 Gs-protein coupled. 5-HT7 Gs-protein coupled. Increasing cellular levels of cAMP. Increasing cellular levels of cAMP. Excitatory Excitatory [edit] Subtypes Within these general classes of serotonin receptors, a number of specific types have been characterized: Rece ptor 5HT1A Gene( s) HTR1 A Distribut ion Function Agonists Antagonists Blood Vessels CNS Addiction [8][9][10] Aggression[11] Anxiety[12] Appetite[13] Blood Pressure[14][15] Cardiovascular Function[16] Emesis[17] Heart Rate[14][15] Impulsivity[18] Memory[19][20] Mood[21] Nausea[17] Nociception[22] Penile Erection[23] Pupil Dilation[24] Respiration[25] Sexual Behavior[26] Sleep[27] Sociability[28] Thermoregulation[29] Vasoconstriction[30] 5-CT 8-OH-DPAT Aripiprazole Buspirone[31] (anxiolytic and antidepressant)[31] Cannabidiol Clozapine Dihydroergotamine Eltoprazine Ergotamine Flesinoxan Flibanserin Gepirone Ipsapirone Methysergide Nefazodone Quetiapine RU 24969 Tandospirone Trazodone Urapidil Xaliproden Alprenolol Asenapine BMY 7378 Cyanopindolol Iodocyanopindolol Lecozotan Methiothepin NAN-190 Oxprenolol Pindolol Propanolol Robalzotan S15535 Spiperone UH-301 WAY-100,135 WAY-100,635 5HT1B HTR1 B Blood Vessels CNS Addiction [32] Aggression[11] Anxiety[33][34][35] Learning[36] Locomotion[37] Memory[36] Mood[35] Penile Erection[23] Sexual Behavior[26] Vasoconstriction 5-CT CP-93,129 CP-94,253 Dihydroergotamine Eltoprazine Ergotamine Methysergide RU 24969 TFMPP Triptans[31] (antimigraine[31]) Zolmitriptan Eletriptan Sumatriptan Alprenolol AR-A000002 Asenapine Cyanopindolol GR 127935 Iodocyanopindolol Isamoltane Metergoline Methiothepin Oxprenolol Pindolol Propanolol SB-216,641 Yohimbine 5HT1D HTR1 D Blood Vessels CNS Anxiety[38][39] Locomotion[37] Vasoconstriction BRL-15572 GR 127935 Ketanserin Metergoline Methiothepin Rauwolscine Ritanserin 5HT1E HTR1E Blood Vessels CNS 5-CT Dihydroergotamine Ergotamine Methysergide Triptans[31] (antimigraine[31]) Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan Yohimbine Eletriptan Methysergide Tryptamine 5HT1F HTR 1F 2C-B 5-MeO-DMT BZP Bufotenin DMT DOM Ergonovine Lisuride LSD Mescaline Myristicin Psilocin Psilocybin TFMPP Atypical antipsychotics Clozapine[31] Olanzapine Quetiapine Risperidone Ziprasidone Aripiprazole Asenapine Cyproheptadine Eplivanserin Etoperidone Iloperidone Ketanserin[31] Blood Vessels CNS GI Tract Platelets PNS Smooth Muscle Addiction (potentially modulating) [40] Anxiety[41] Appetite Cognition Imagination Learning Memory Mood Perception Sexual Behavior[42] Sleep[43] Thermoregulation[44] Methiothepin Vasoconstriction[45] Yohimbine (antihypertensive[31] ) Methysergide Mianserin Mirtazapine Nefazodone Pimavanserin Pizotifen Ritanserin Trazodone 5HT2A HTR2 A Blood Vessels CNS GI Tract Platelets PNS Smooth Muscle Addiction (potentially modulating) [40] Anxiety[41] Appetite Cognition Imagination Learning Memory Mood Perception Sexual Behavior[42] Sleep[43] Thermoregulation[44] Vasoconstriction[45] 2C-B 5-MeO-DMT BZP Bufotenin DMT DOM Ergonovine Lisuride LSD Mescaline Myristicin Psilocin Psilocybin TFMPP Yohimbine Atypical antipsychotics Clozapine[31] Olanzapine Quetiapine Risperidone Ziprasidone Aripiprazole Asenapine Cyproheptadine Eplivanserin Etoperidone Iloperidone Ketanserin[31] (antihypertensive[31]) Methysergide Mianserin Mirtazapine Nefazodone Pimavanserin Pizotifen Ritanserin Trazodone 5HT2B HTR2 B Blood Vessels CNS GI Tract Platelets PNS Smooth Muscle Anxiety[46][47][48] Appetite[49] Cardiovascular Function GI Motility[50] Sleep[43] Vasoconstriction BW-723C86 Fenfluramine MDMA Norfenfluramine Ro60-0175 Agomelatine Asenapine BZP Ketanserin Methysergide Ritanserin Tegaserod Yohimbine 5HT2 HTR2 C Blood Vessels CNS A-372,159 AL-38022A Aripiprazole Agomelatine[31] (antidepressant[31]) Asenapine C Addiction. (potentially GI Tract Platelets PNS Smooth Muscle modulating)[40] Anxiety[51][52][53] Appetite GI Motility[54] Locomotion Mood[53][52] Penile Erection[55][56] Sexual Behavior[42] Sleep[57] Thermoregulation[44] Vasoconstriction Ergonovine Lorcaserin Ro60-0175 TFMPP Trazodone[31] (hypnotic[31]) YM-348 Clozapine[31] (antipsychotic[31]) Cyproheptadine Dimebolin Eltoprazine Etoperidone Fluoxetine Iloperidone Ketanserin[31] (antihypertensive[31] ) Lisuride Methysergide[58] Mianserin Mirtazapine Nefazodone Olanzapine Quetiapine Risperidone Ritanserin Trazodone Alosetron Several antiemetics[31] Dolasetron Ondansetron[31] Granisetron Tropisetron Clozapine Memantine Metoclopramide Mianserin Mirtazapine Olanzapine Quetiapine L-Lysine[60] Piboserod 5HT3 HTR3 CNS A GI Tract HTR3 PNS B HTR3 C HTR3 D HTR3E Addiction Anxiety Emesis GI Motility Learning[59] Memory[59] Nausea 2-Methyl-5-HT BZP Quipazine RS-56812 5HT4 HTR4 Anxiety[60][61] Appetite[62][63] GI Motility Learning[64][65] Memory[66][65][67] Mood[68][69] Respiration[70] 5-MT BIMU-8 Cinitapride Cisapride[31] (gastroprokinetic) Dazopride Metoclopramide Mosapride Prucalopride RS-67333 Renzapride Tegaserod CNS GI Tract PNS 5HT5A HTR5 A CNS Locomotion[71] Sleep[72] 5-CT Ergotamine Valerenic Acid[72] Asenapine Dimebolin Methiothepin Ritanserin SB-699,551 SB-699,551-A 5HT6 HTR6 CNS Anxiety[73][74] Cognition[75] Learning[76] Memory[76] Mood[74][77] EMD-386,088 EMDT Aripiprazole Asenapine Clozapine Dimebolin EGIS-12233 Iloperidone MS-245 Olanzapine Ro04-6790 SB-258,585 SB-271,046[78] SB-357,134 SB-399,885 5HT7 HTR7 Blood Vessels CNS GI Tract Anxiety[79][80] Memory[81][82] Mood[79][80] Respiration[25][83] Sleep[79][83][84] Thermoregulation Vasoconstriction 5-CT 8-OH-DPAT AS-19 Aripiprazole Asenapine Clozapine EGIS-12233 Iloperidone Ketanserin Olanzapine Ritanserin SB-269,970 Note that there is no 5-HT1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT2 family of receptors and was redesignated as the 5-HT2C receptor. Note that there is also no 5-HT5B receptor, as it exists only in mice and rats and not in humans or monkeys. Very nonselective agonists of 5-HT receptor subtypes include ergotamine (an antimigraine), which activates 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors.[31] LSD (a psychedelic) is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist.[31] Serotonin (5-hydroxytryptamine, 5-HT) is a key mediator in the physiology of mood, vascular function and gastrointestinal motility. This explains the number of therapeutic agents that act targeting the serotonergic system such as: 5-HT3 antagonists, SSRIs and triptans. This post will focus on the classification of serotonin receptors, as well as drug classes that act on serotonergic transmission. This includes 5-HT agonists, antagonists and medications that modulate 5-HT at the presynaptic level, all of them of very high clinical relevance. Overdose of a combitation of serotonergic agents can lead to serotonin syndrome. Outline: Serotonin receptors Drugs acting on serotonergic transmission: MAO inhibitors, SNRIs, SSRIs Serotonin agonists Serotonin antagonists Serotonin receptors classification Based on biochemical and pharmacological criteria, serotonin receptors are classified into seven main receptor subtypes, 5-HT1–7. Of major pharmacotherapeutic importance are those designated 5-HT1, 5-HT2, 5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the 5-HT3 subtype represents a ligand-gated ion channel. 5-HT1 receptors are subdivided into 5-HT1A, 5-HT1B, and 5-HT1D receptors; while 5-HT2 subtypes include 5-HT2A, 5-HT2B, and 5-HT2C. Drugs acting on serotonergic transmission The figure above depicts how serotonin neurotransmission may be modified at the presynaptic level by inhibiting degradation, storage or reuptake. MAO inhibitors Monoamine oxidase is a key enzyme for serotonin, dopamine and norepinephrine inactivation. MAO inhibitors prevent inactivation of monoamines within a neuron, causing excess neurotransmitter to diffuse into the synaptic space. This class of agents is used in the treatment of depression (phenelzine, tranylcypromine, selegiline) and Parkinson’s disease (selegiline). Dietary restrictions (because of tyramine toxicity) limit their widespread use. Inhibitors of serotonin storage They interfere withe the ability of synaptic vesicles to store monoamines; displace serotonin, dopamine and norepinephrine from their storage in presynaptic nerve terminals. Agents that share this mechanism of action include amphetamine, methylphenidate and modafinil. Serotonin-norepinephrine reuptake inhibitors (SNRIs) SNRIs mechanism involves blockade of 5-HT and norepinephrine reuptake in a concentrationdependent manner. Agents in this class include venlafaxine and duloxetine, they may be effective for the treatment of depression in patients in whom SSRIs are ineffective. Selective serotonin reuptake inhibitors (SSRIs) SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and to an enhanced postsynaptic neuronal activity. Tricyclic-antidepressants (TCAs) Tricyclic antidepressants act by inhibiting reuptake of 5-HT and norepinephrine from the synaptic cleft by respectively blocking 5-HT and norepinephrine reuptake transporters, thereby causing enhancement of postsynaptic response. Serotonin receptor agonists Serotonin receptors agonists have wide clinical applications, from treatment of depression to abortive medications for migraine headache. According to the receptor they activate, they can be divided into: 5-HT1A agonists Buspirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety and depression. 5-HT1B and 5-HT1D agonists The “triptans” are a drug class useful as abortive medication for the treatment of acute migraine headaches. They are very effective medications that bind to 5-HT1B and 5-HT1D receptors in cranial vessels, which leads to vasoconstriction and decreased release of neuropeptides involved in “sterile inflammation”. 5-HT2C agonist Trazodone was previously believed to be a 5-HT2C receptor antagonist. However, recent publications report that trazodone would behave as a 5-HT2C agonist. This drug is used generally as somnorific. 5-HT4 agonists Cisapride is a serotonin and cholinergic agonist used as a prokinetic drug, it was withdrawn from the U.S. market because of cardiovascular toxicity. Non-selective agonists Ergotamine activates a more than one subtype of 5-HT receptor, it binds to 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. Its vasoconstrictor effect makes it a suitable treatment for migraine attacks. LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist that has psychedelic properties. Serotonin receptor antagonists 5-HT2 antagonists Ketanserin is a 5-HT2A/2C antagonist used for the treatment of hypertension. In addition to its serotonin antagonism, it has affinity for alpha-1 receptors, which may contribute to its antihypertensive effect. Clozapine is an atypical antipsychotic drug that acts as 5-HT2A/2C receptor antagonist with high affinity for dopamine receptors. It represents a class of atypical antipsychotic drugs, one key advantage of this group is its reduced incidence of extrapyramidal side effects compared to the classical antipsychotics, and possibly a greater efficacy for reducing negative symptoms of schizophrenia. Agomelatine is a new antidepressant with agonist action at the melatonin receptor and antagonism at the 5-HT2C receptor. 5-HT3 antagonists This class includes drugs such as ondansetron, palonosetron and others. These agents are particularly useful in the treatment of chemotherapy induced nausea and vomiting (CINV). www.facebook.com/dar.ovais