Synthesis of novel succinamide derivatives having the 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton as potent and selective M2 muscarinic receptor antagonists. I.
A series of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one derivatives containing the succinamide skeleton has been synthesized and evaluated for M1, M2 and M3 muscarinic receptor binding affinities (in vitro) and M2 and M3 muscarinic receptor antagonistic activities (in vivo). Some of them showed higher and more selective binding affinities for M(2) muscarinic receptors than that of AF-DX 116. Among them, 11-[3-[N-[2-(N-benzyl-N- methylamino)ethyl]-N-ethylcarbamoyl]propionyl]-5,11-dihydro-6H-pyr ido [2,3-b][1,4]benzodiazepin-6-one (68) was found to be the most potent and selective M2 muscarinic receptor antagonist in vitro. This compound also strongly inhibited the oxotremorine-induced bradycardia after intravenous administration and showed 130-fold selectivity for M2 muscarinic receptors over M3 muscarinic receptors in vivo.
Watanabe
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki Japan.
Kinoyama
I
I
Kakefuda
A
A
Okazaki
T
T
Takizawa
K
K
Hirano
S
S
Shibata
H
H
Yanagisawa
I
I
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008956:Models, Chemical; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012472:Salivation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013386:Succinates
D000577:Amides; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D013386:Succinates; D001569:Benzodiazepines; C011116:succinamide