Synthesis and receptor binding of new thieno[2,3-d]pyrimidines as selective ligands of 5-HT3 receptors

With the aim to develop new potent and selective ligands of 5-HT3-type serotonin receptors andto acquire more information on their structure-affinity relationships, new thieno[2,3-d]pyrimidinederivatives 32–39 were synthesized and their binding to 5-HT3 versus 5-HT4 receptors wasstudied. Some of these new compounds exhibit good affinity for cortical 5-HT3 receptors, but notfor 5-HT4 receptors. Among these derivatives, 6-ethyl-4-(4-methyl-1-piperazinyl)-2-(methylthio)-thieno[2,3-d]pyrimidine 32 is the most potent ligand (Ki = 67 nM); it behaves as a competitiveantagonist of the 5-HT3 receptor function in the guinea pig colon. Its binding interactions with5-HT3A receptors were analysed by using receptor modelling and comparative docking.