SELECTIVE MUSCARINIC ANTAGONISTS - II - SYNTHESIS AND ANTIMUSCARINIC PROPERTIES OF BIPHENYLYLCARBAMATE DERIVATIVES

A novel series of biphenylylcarbamate derivatives were synthesized and evaluated for binding to M-1, M-2 and M-3 receptors and for antimusca rinic activities. Receptor binding assays indicated that biphenyl-2-yl carbamate derivatives had high affinities for M-1 and M-3 receptors an d good selectivities for M-3 receptor over M-2 receptor, indicating th at the biphenyl-2-yl group is a novel hydrophobic replacement for the benzhydryl group in the muscarinic antagonist field. In this series, q uinuclidin-1-yl biphenyl-2-ylcarbamate monohydrochloride (81, YM-46303 ) exhibited the highest affinities for M-1 and M-3 receptors, and sele ctivity for M-3 over M-2 receptor. Compared to oxybutynin, YM-46303 sh owed approximately ten times higher inhibitory activity on bladder pre ssure in reflexly-evoked rhythmic contraction, and about 5-fold greate r selectivity for urinary bladder contraction against salivary secreti on in rats. Moreover, selective antagonistic activity was also observe d in vitro. Further evaluation of antimuscarinic effects on bradycardi a and presser in pithed rats, and on tremor in mice, showed that YM-46 303 can be useful for the treatment of urinary urge incontinence as a bladder-selective M-3 antagonist with potent activities and fewer side effects.