179328-88-2Relevant articles and documents
Synthesis of novel succinamide derivatives having a 5,11-dihydro-6h- pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton as potent and selective M2 muscarinic receptor antagonists. II
Watanabe, Toshihiro,Kakefuda, Akio,Kinoyama, Isao,Takizawa, Kenji,Hirano, Seiko,Shibata, Hiroshi,Yanagisawa, Isao
, p. 1458 - 1469 (2007/10/03)
A series of succinamide derivatives containing the 5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton (6a-z) was prepared and evaluated for binding affinity to muscarinic receptors in vitro and for antagonism of bradycardia and salivation in vivo in comparison with AF-DX 116 (1a). Structure-activity relationships (SAR) studies in vitro indicated that the 4-(4-alkyl-1-piperazinyl)benzylamino moiety plays a crucial role in enhancing the infinity for M2 muscarinic receptors. Compound 6y, containing a 4-(4-isopropyl-1-piperazinyl)benzylmethylamino moiety, exhibited the highest affinity for M2 muscarinic receptors (pK(i) = 9.2), being 200 times as potent as 1a, and compound 6u, containing a 4-(4-ethyl-1- piperazinyl)benzylethylamino moiety, showed the highest selectivity for M2 over M3 muscarinic receptors (M3/M2 ratio=320). Both 6y and 6u antagonized the oxotremorine-induced bradycardia in rats after intravenous or oral administration. Oral evaluation in conscious dogs showed that the efficacy for increasing the heart rate was at least 3-fold greater than that of 1a.
