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

• Published in: Chemical & pharmaceutical bulletin Vol. 45; no. 6; pp. 996 - 1007
• Main Authors: WATANABE, Toshihiro, KINOYAMA, Isao, KAKEFUDA, Akio, OKAZAKI, Toshio, TAKIZAWA, Kenji, HIRANO, Seiko, SHIBATA, Hiroshi, YANAGISAWA, Isao
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 1997; Maruzen; Japan Science and Technology Agency
• Subjects: AF-DX 116; Amides - chemistry; Amides - pharmacology; Animals; Antiarythmic agents; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Biological and medical sciences; bradycardia; Cardiovascular system; Heart Rate - drug effects; Male; Medical sciences; Models, Chemical; Muscarinic Antagonists - chemical synthesis; Muscarinic Antagonists - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Receptor, Muscarinic M2; Receptors, Muscarinic - metabolism; Salivation - drug effects; selective M2 muscarinic receptor anatagonist; Structure-Activity Relationship; succinamide; Succinates; Heart; Intravenous administration; Rat; Arrhythmia; Nitrogen heterocycle; Lactam; Cardiovascular disease; M2 receptor; Selectivity; Cholinergic receptor; Structure activity relation; Heart disease; Dicarboxylic acid; Aromatic compound; Antagonist; Chemical synthesis; Rodentia; Tricyclic compound; In vitro; Heart rate; In vivo; Vertebrata; Bradycardia; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Affinity; Carboxamide
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.45.996

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 M2 muscarinic receptors than that of AFDX 116. Among them, 11-[3-[N-[2-(N-benzyl-N-methylamino)ethyl]-N-ethylcarbamoyl]propiony]-5, 11-dihydro-6H-pyrido[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.