Inhibition of the 5-hydroxytryptamine receptor (5-HT3R), a member of the Cys-loop superfamily ofLigand-Gated Ion Channels (LGICs), has been recognized to have important antiemetic effects. Withrespect to the many other drugs already in use, such as the first generation 5-HT3R antagonist granisetron,palonosetron, a second generation antagonist, clearly demonstrates superior inhibition potencytowards the 5-HT3Rs. Five different receptor monomers, the 5-HT3R AeE, have been identified althoughthe A and B subunits are the only known to build functional receptors, the homopentameric 5-HT3AR andthe heteropentameric 5-HT3BeAR (with BBABA subunit arrangement). At present, however, no threedimensionalstructure has been reported for any of the 5-HT3R subunits. To understand the bindingproperties of agonists and antagonists, models of the extracellular portion of the 5-HT3R A and B subunitsare built and assembled into the receptor (homo- and hetero-) pentameric structure on the basis of theknown three-dimensional structure of the nicotinic-acetylcholine receptor (nACh-R). The results ofdocking studies of the natural agonist serotonin and the antagonists palonosetron and granisetron intothe modelled homomeric and heteromeric 5-HT3R binding interfaces, provide a possible rationalizationboth of the higher potency of palonosetron with respect to other antagonists, and of its previouslyreported allosteric binding and positive cooperativity properties

Computational analysis of ligand recognition sites of homo- andheteropentameric 5-HT3 receptors / Moura Barbosa, Armenio Jorge; De Rienzo, Francesca; M. J., Ramos; Menziani, Maria Cristina. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 45(2010), pp. 4746-4760. [10.1016/j.ejmech.2010.07.039]

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