Cholinergic agents structurally related to furtrethonium. 1

Article abstract of DOI:10.1016/0223-5234(94)90213-5

A series of 5-substituted-2-(dimethylaminomethyl)-furyl derivatives 4 was prepared, with the aim of discovering novel antimuscarinic agents which are selective for smooth muscle as opposed to cardiac tissue.Both non-quaternary and quaternary ammonium compounds were synthesised.The agonist starting point, furtrethonium 3, was gradually transformed into antagonist by introduction of lipophilic and bulky groups in position 5 of this molecule.In particular, the introduction of α-hydroxy-α-cyclohexylbenzyl moiety (compound 9b), a lipophilic group characteristic ofantimuscarinic agents, caused an appreciable increase of the antagonist's potency, and the lengthening of the distance between this lipophilic group and the furan ring, obtained by introduction of an ester, ether or amide group, led to some selectivity towards smooth muscle (compounds 19, 21, 25).Interestingly, compound 19, with an ester moiety as a spacer group, proved to be at least 20 times more potent in rat ileum (pK_B = 7.3) and rat bladder (pK_B = 7.2) than guinea-pig atria (pK_B = 5.9). furtrethonium derivatives / cholinergic agents / antimuscarinic activity