Selective muscarinic antagonists. I. Synthesis and antimuscarinic properties of 4-piperidyl benzhydrylcarbamate derivatives.
A series of 1-substituted-4-piperidyl benzhydrylcarbamate derivatives were synthesized and evaluated for binding affinity to M1, M2 and M3 receptors, and for antimuscarinic activities. Receptor binding assays indicated that 1-benzyl-4-piperidyl benzhydrylcarbamate derivatives showed higher affinities for M1 and M3 receptors, and good selectivities for M3 over M2 receptor, than the corresponding ester analog. These results indicate that the urethane bond is a novel linker for muscarinic antagonists, and serves to lock the molecular conformation and allows the hydrophobic portion and cationic site of the molecule to bind to M1 and M3 muscarinic receptors. Among the prepared compounds, 1-(4-methylaminobenzyl)-4-piperidyl benzhydrylcarbamate monohydrochloride (18b, YM-58790) exhibited potent inhibitory activity on bladder pressure in reflexly-evoked rhythmic contraction, comparable to oxybutynin and was approximately ten times less inhibitory on oxotremorine-induced salivary secretion than oxybutynin in rats. Further evaluation of antimuscarinic effects on bradycardia and pressor in pithed rats, and on tremor in mice, demonstrated that YM-58790 can be useful for treatment of urinary urge incontinence as a bladder-selective M3 antagonist with 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; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D002219:Carbamates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D001743:Urinary Bladder / Q000187:drug effects; D014549:Urinary Incontinence / Q000188:drug therapy
D001559:Benzhydryl Compounds; D002219:Carbamates; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic