5-HTs receptor

It has been suggested that high affinity for certain 5-HT receptors is a possible method for reducing extrapyramidal side effects observed with antipsychotics. LiabiUty for extrapyramidal side effects has been hypothesi2ed to be related to the ratio of the affinity between dopamine receptor... 

Reaction of tetrahydroquinoline 257 with ethyl bromopyruvate afforded pyrroloquinoline 260 which upon transesterification by treatment with tropine in presence of sodium methoxide in toluene gave 261 which was found to be useful as 5-HT receptor antagonist (89EP322016). 

Serotonin agonists G-protein coupled 5-HT receptors 5-HT3 ion channels cAMP (5-HT-,) t cAMP (5-HT4 7) t PLC (5-HT2) l Release of excitatory neuropeptides l Neurogenic inflammation f vasoconstriction Myocardial infarction, stroke, peripheral vascular occlusion... 

Serotoninergic System. Figure 1 Graphical representation of the current classification of 5-hydroxytryptamine (5-HT) receptors. Receptor subtypes represented by shaded boxes and lowercase designate receptors that have not been demonstrated to definitively function in native systems. Abbreviations 3-5r cyclic adenosine monophosphate (cAMP) phospholipase C (PLC) negative (-ve) positive (+ve)... 

Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38... 

Hoyer D, Hannon J, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71 533—554... 

Amino acid receptors Monoamine receptors Lipid receptors Purine receptors Neuropeptide receptors Peptide hormone receptors Chemokine receptors Glycoprotein receptors Protease receptors Metabotropic glutamate and GABAb receptors Adrenoceptors, dopamine and 5-HT receptors, muscarinic and histamine receptors Prostaglandin, thromboxane and PAF receptors Adenosine and ATP (P2Y) receptors Neuropeptide Y, opiate, cholecystokinin VIP, etc. Angiotensin, bradykinin, glucagon, calcitonin, parathyroid, etc. Interleukin-8 TSH, LH/FSH, chorionic gonadotropin, etc. Thrombin... 

Table 9.3 Behavioural and physiological responses affected by 5-HT receptors...

It is obvious that strenuous efforts have been invested in the research of 5-HT receptors and, in particular, in the development of receptor-selective agonists and antagonists. All this has been done in the hope that it might be possible to control a specific switch in the brain that governs a particular aspect of 5-HT function and which would be beneficial therapeutically. A further ambition is that, by avoiding activation of other 5-HT receptors, the risk of any unwanted side-effects would be eliminated. Of course, it is equally possible that reduction in non-specific receptor interactions could actually unmask some side-effects. 

What the overall physiological consequences of either an increase or decrease in 5-HT transmission in any brain region might be is beyond the scope of this chapter. However, it is certain that the diverse cocktail of 5-HT receptors in every brain region gives scope for flexibility and refinement in the 5-HT response that would not be possible if there were only the two receptors identified by Gaddum. This flexibility applies not only to the qualitative features of the response but also its duration. Another dimension of sophistication is added by the different affinities of 5-HT for each of its receptors and differences in their rates of desensitisation. An interesting discussion of how all these variables could affect overall 5-HT transmission in the brain can be found in Uphouse (1997). 

Boadle-Biber, MC (1993) Regulation of serotonin S5mthesis. Prog. Biophys. Molec. Biol. 60 1-15. Curzon, G, Gibson, EL and Oluyomi, AO (1997) Appetite suppression by commonly used drugs depends on 5-HT receptors but not on 5-HT availability. Trends Pharmacol. Sci. 18 21-25. Gaddum, JH and Picarelli, ZP (1957) Two kinds of tr5 ptamine receptor. Brit. J. Pharmacol. 12 323-328. (Reproduced in Brit. J. Pharmacol. 120 (Suppl) 134-139.)... 

Possibly there is a subclass of 5-HT receptors that would be preferentially activated by tryptamine if its endogenous concentrations were ever adequate. Indeed the term tryptamine receptor as first used by Gaddum to describe the effects of all indole amines may be one to which we should return. 

Some neuroleptics, including clozapine, are potent 5-HT-receptor antagonists and the possible role of 5-HT in the action of neuroleptics and the development of schizophrenia has recently generated much interest (Busatto and Kerwin 1997). This has centred primarily on 5-HT2A receptors found in the limbic cortex, which are linked to neuronal excitation and believed to mediate the hallucinogenic effects of drugs such as lysergic acid diethylamide (LSD). 

Currently, hopes for compounds with greater clinical efficacy and faster onset of action than buspirone rest on the development of selective ligands for 5-HT receptors. So far, antagonists of 5-HT2a/c (e-g- ritanserin), 5-HTs (e.g. ondansetron) and 5-HT4 (e.g. zacopride) receptors have all been explored but their anti-anxiety effects are, at best, equivocal. Full appraisals of the role of 5-HT systems in anxiety and the actions of anti-anxiety drugs are to be found in Handley (1995), Barnes and Sharp (1999) and Olivier, van Wijngaarden and Soudijn (2000). 

Deakin, JFW, Graeff, FG and Guimaraes, FS (1992) 5-HT receptor subtypes and the modulation of aversion. In Central Serotonin Receptors and Psychotropic Drugs (Eds Marsden, CA and Heal, DJ), Blackwell Scientific Publications, Oxford, pp. 147-174. 

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