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

Article abstract of 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 AF-DX 116. Among them, 11-[3-[N-[2-(N- benzyl-N-methylamino)ethyl]-N-ethylearbamoyl]propionyl]-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.

Full text of DOI:10.1248/cpb.45.996

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