5--HT Recepttorrss and Ttheiirr Liigandss

Peter J. Pauwels Centre d'Immunologie Pierre Fabre, 5, avenue Napo léon III B.P . 497, F-74164 Saint-Julien-en-Genevois Cedex, France Peter Pauwels is Research Director of Centre d’Immunologie Pierre Fabre at Saint-Julien en Genevois in France. His research includes the molecular pharmacology of 5-HT receptors, in particular the mechanisms governing ligand efficacy and diverse signalling via single receptor subtypes. Serotonin (5-hydroxytryptamine, 5-HT) produces its effects through a variety of membrane-bound receptors. 5-HT and its receptors are found both in the central and peripheral nervous system (CNS/PNS), as well as in a number of non- neuronal tissues in the gut, cardiovascular system and blood. 5-HT has been implicated in the aetiology of numerous disease states, including depression, anxiety, social phobia, schizophrenia, obsessive-compulsive and panic disorders; in addition to migraine, hypertension, pulmonary hypertension, eating disorders, vomiting and irritable bowel syndrome. Except for the 5-HT receptor , which is a ligand-gate d ion channel, 5-HT receptors belong to the G protein-coupled receptor (GPCR) superfamily and, with at least fourteen distinct members, represent one of the most complex families of neurotransmitter receptors (Tables 1, 2). Splice var ian ts ( 5-HT 5-HT , 5- ht 5-HT ) an d RNA edit ed iso forms (5 -HT ) have b een de scrib ed, whilst there is evidence that amongst the heptahelical 5-HT receptors, homo- and heter odime risati on (5- HT ) can occ ur. It should also be noted that there is emerging evidence that 5-HT receptor subtypes have 3 3 4 6 7 2C 1B,1D , , Introduction naturally occurring polymorphic variants, and these could be an additional source of biological variation within the 5-HT system. Current efforts pursue the identification of either efficacious or silent ligands with high selectivity for the different receptor subtypes. The issue of ligand efficacy is both complex and difficult to improve as we know today that ligands may display a wide spectrum of activities: efficacious to partial agonism, silent neutral antagonism, partial to efficacious inverse agonism (Table 3), or in some case s protean ag onism. Although it is well established that different agonists do not necessarily elicit the same magnitude of response, it is less clear whether these agonists also differentiate between various possible sign al t rans ducti on pat hway s. Such diff eren tial sig nalli ng a sin gle rec ept or sub type is an intriguing issue in molecular pharmacology and emphasizes that a single receptor target could be activated in different ways. Consequently, it would be possible to obtain agonists with properties that are both and distinct. It is anticipated that both efficacious and selective receptor probes will provide tools to advance definition of functional effects , be it or , and, in addition, lead to more efficacious drug treatments with fewer side effects for a variety of disorders. Molecular genetic approaches offer a 1 1,2 via quantitatively qualitatively in situ in vitro in vivo Tocris Cookson Inc., USA Tel: (800) 421-3701 Fax: (800) 483-1993 [email protected] [email protected] Tocris Cookson Ltd., UK Tel: + 44 (0)117 916 3333 Fax: + 44 (0)117 916 3344 [email protected] [email protected] www.tocris.com 5-HT Receptors and their Ligands 5-HT Receptors and their Ligands Table 1. Different 5-HT receptor subtypes 5-HT 5-HT 5-HT 5-HT 5-ht 5-ht 5-HT 1 2 3 4 5 6 7 Subtypes 5-HT , 5-HT , 5-HT , 5-HT , 5-HT , 5-HT , 5-HT 5-ht , 5-ht 5-ht , 5-ht 5-HT Major signalling cAMP IP Ion channel cAMP cAMP? 1A 1B 1D 2A 2B 3A 3B 5A 5B 1E 1F 2C 3 ¯ cAMP cAMP pathway Fluoxetine hydrochloride (Cat. No. 0927) Citalopram hydrobromide (Cat. No. 1427) (Bold text denotes compounds available from Tocris) Figure 1. Structures of some 5-HT uptake inhibitors

5--HT Recepttorrss and Ttheiirr Liigandss

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