Selective muscarinic antagonists. II. Synthesis and antimuscarinic properties of biphenylylcarbamate derivatives

Article abstract of DOI:10.1248/cpb.46.1286

A novel series of biphenylylcarbamate derivatives were synthesized and evaluated for binding to M₁, M₂ and M₃ receptors and for antimuscarinic activities. Receptor binding assays indicated that biphenyl-2-ylcarbamate derivatives had high affinities for M₁ and M₃ receptors and good selectivities for M₃ receptor over M₂ receptor, indicating that the biphenyl-2-yl group is a novel hydrophobic replacement for the benzhydryl group in the muscarinic antagonist field. In this series, quinuclidin-4-yl biphenyl-2-ylcarbamate monohydrochloride (81, YM-46303) exhibited the highest affinities for M₁ and M₃ receptors, and selectivity for M₃ over M₂ receptor. Compared to oxybutynin, YM-46303 showed approximately ten times higher inhibitory activity on bladder pressure in reflexly-evoked rhythmic contraction, and about 5-fold greater selectivity for urinary bladder contraction against salivary secretion in rats. Moreover, selective antagonistic activity was also observed in vitro. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, showed that YM-46303 can be useful for the treatment of urinary urge incontinence as a bladder-selective M₃ antagonist with potent activities and fewer side effects.

Full text of DOI:10.1248/cpb.46.1286

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