Search

Few muscarinic antagonists differentiate between the M4and M2muscarinic receptors. In a structure–activity study, aimed at discovering leads for the development of a M4muscarinic receptor-selective antagonist, we have synthesized and tested at cloned muscarinic receptors the binding of a group of dioxolane- or oxadiazole-dialkyl amines, and compared them to our compound 1, which contains the furan nucleus. Although none of these agents were particularly potent at M4receptors (Kdvalues were typically 30–70nM), furan derivatives (−)1and (+)1were significantly more potent at M4receptors than at M2receptors (∼3- and 4-fold, respectively). The dioxolane derivatives 12band 12cwere more than 10-fold selective for the M4versus the M2receptors, while the dioxolane derivative 12ewas 15-fold more potent at M4receptors than for M2receptors. However, these agents bound to M3receptors with potencies like that for the M4receptor, so they are not M4-selective. The M4/M2relative selectivities of some of our compounds are similar to the better hexahydrosiladifenidol derivatives, and may provide some important structural clues for the development of potent and selective M4antagonists.