Selective muscarinic antagonists. II. Synthesis and antimuscarinic properties of biphenylylcarbamate derivatives.
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 (8l, 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.
Naito
R
R
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Takeuchi
M
M
Morihira
K
K
Hayakawa
M
M
Ikeda
K
K
Shibanuma
T
T
Isomura
Y
Y
D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006321:Heart / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000145:classification / Q000187:drug effects / Q000378:metabolism; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D001713:Biphenyl Compounds; D002219:Carbamates; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic