Computational analysis of ligand recognition sites of homo- andheteropentameric 5-HT3 receptors

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