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.
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 affinity for M2 muscarinic receptors. Compound 6y, containing a 4-(4-isopropyl-1-piperazinyl)benzylmethylamino moiety, exhibited the highest affinity for M2 muscarinic receptors (pKi = 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.
Watanabe
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Kakefuda
A
A
Kinoyama
I
I
Takizawa
K
K
Hirano
S
S
Shibata
H
H
Yanagisawa
I
I
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D001570:Benzodiazepinones / Q000737:chemistry*; D004285:Dogs; D008401:Gas Chromatography-Mass Spectrometry; D006339:Heart Rate / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D012472:Salivation / Q000187:drug effects; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D013386:Succinates
D000577:Amides; D001570:Benzodiazepinones; D018727:Muscarinic Antagonists; D013386:Succinates; C011116:succinamide