Serotonin receptors classes

Serotonin is unsurpassed among monoamine neurotransmitters in the number of receptor subtypes reported to-date. Fourteen subtypes of seven major serotonin receptor classes have been identified in the central nervous system, the peripheral nervous system, myeloid/immune cell types, and smooth musculature of mammals [1]. While discreet, endogenous release of serotonin is able to manifest a variety of responses and behaviours, exogenous administration of serotonin (and nonselective mimetics) suffers from indiscriminate actions at all populations of accessible receptors. Hence, the discovery of subtype-specific agonists and/or antagonists to the various serotonin receptors have been sought as specific therapeutic agents. 

The authors also identified the most common structural motifs unique to ligands of individual classes of GPCRs such as the adrenergic, dopamine, histamine, muscarinic, and serotonin receptors as shown in Table 1. 

Three families of serotonin receptor, the 5-HT family, the 5-HT2 family and the family that includes the 5-HT4, 5-ht6 and 5-HT7 receptors represent the three major classes of 5-HT receptor that are G-protein-coupled receptors (Ch. 19). The 5-HT3 receptor is a ligand-gated ion channel and is a separate family. Although each serotonin receptor can be potently activated by 5-HT, differences insignal transduction mechanisms,neuroanatomical distribution and affinities for synthetic chemicals create opportunities for drug discovery and make each 5-HT receptor subtype a potential therapeutic target. 

A therapeutic alternative for treatment of anxiety and depression is the use of 5-HT1A agonists. Azapirones comprise the major class of 5-HT1A agonists of which buspirone (Buspar [4]) is the only FDA-approved 5-HT1A selective agonist (relative to the other 13 serotonin receptor subtypes) for anxiety currently on the US market (Scheme 19.1). Buspirone has shown efficacy in randomized controlled trials of GAD for which it was approved [5-7]. Unlike benzodiazepines, buspirone is not addictive... 

Two general classes of alkaloids are distinguished in ergot amine alkaloids and amino acid alkaloids (table 5.9) (Peroutka 1996). While the amine alkaloids are selective for antagonist effects on serotonin receptors, the amino acid alkaloids are less selective and act upon other monoamine receptors. The constituents of interest for cognitive enhancement are predominantly the amine alkaloids. 

Serotonin receptors. Based on biochemical and pharmacological criteria seven receptor classes can be distinguished. Of major pharmacotherapeutic importance are those designated 5-HTi, 5-HT2,5-HT4, and 5-HT7, all of which are G-protein-coupled, whereas the 5-HT3 subtype represents a ligand-gated non-selective cation channel. 

In contrast, receptors in the second group have a low affinity [micromolar range] for serotonin and have been divided into three different classes— named S-HTj, S-HTj, and 5-HT4—with specific pharmacological properties [Miquel and Hamon 1992]. The S-HTj receptor [with subgroups 5-HT2A, S-HTjb, and S-HTjc] mediates facilitatory effects of serotonin, whereas the 5-HT3 receptor is the only serotonin receptor that directly activates an ion channel and therefore provides rapid activation of target cells. 

Atypical neuroleptics. Because of the limited effectiveness and safety of conventional neuroleptics in TS, clinicians have turned to a new generation of neuroleptics that have been introduced for the treatment of schizophrenia. Risperidone, a member of a class of antipsychotics that blocks both DA and serotonin receptors, has been established as superior to placebo and equal, or superior, to haloperidol in the treatment of schizophrenia (Chouinard et al. 1993 Marder and Meibach 1994]. Risperidone has a more favorable side-effect profile than that of conventional neuroleptics and may have less potential for producing tardive dyskinesia. Compared with haloperidol, fewer extrapyramidal side effects are observed with risperidone in doses of 6 mg/ day or less. As encouraging reports appear in the literature (Lombroso et al. 1995 Stamenkovic et al. 1994 van der Linden et al. 1994], risperidone is currently being widely used by clinicians to treat tic disorders. 

There are two main families of ligand-gated ion channel proteins that act as ionotropic receptors. One family includes the nicotinic acetylcholine receptor, the GABA-A receptor, the glycine receptor, and a class of serotonin receptor. The other family comprises various types of ionotropic glutamate receptors. Since these various ligand gated ion channels are activated by neurotransmitters, the medicinal chemistry of these proteins is presented in detail in chapter 4. 

The ratio between the blockade of serotonin receptors and dopamine receptors differs for various classes of antipsychotic drugs. True or False. 

The 5-hydroxytryptamine3 (5-HT3) receptor contains an integral, agonistgated ion channel and in this way differs from all other known serotonin receptors whose actions are mediated via G proteins (1). 5-HT3 receptors were one of the original two classes of serotonin-activated receptors defined by Gaddum and Picarrelli (2). Seven distinct classes have now been defined, but, to date, the 5-HT3 receptor is the only vertebrate 5-HT-gated ion channel known indeed, it is more closely related to the nicotinic acetylcholine (nACh) receptor than to any of these other classes of 5-HT receptor. 

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