- Tricyclic Compounds as Selective Muscarinic Receptor Antagonists. 3. Structure-Selectivity Relationships in a Series of Cardioselective (M2) Antimuscarinics
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On the basis of the cardioselective muscarinic receptor antagonist AF-DX 116 (2), a series of 11-substituted pyridobenzodiazepinones (9-35) was prepared and screened for their binding affinity to muscarinic receptors located in cardiac (M2) and glandular (M3) tissue.The ratio of IC50 values of the test compounds in the two different tissues was taken as a measure of cardiac (M2) receptor selectivity.Qualitative structure-selectivity relationships point to the fact that it is the spartial orientation of the protonated side-chain nitrogen atom in relation to the tricycle that is the main determinant for receptor subtype recognition and hence is important for the achievement of cardiac (M2) selectivity.
- Engel, Wolfhard W.,Eberlein, Wolfgang G.,Mihm, Gerhard,Hammer, Rudolf,Trummlitz, Guenter
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p. 1718 - 1724
(2007/10/02)
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- CONDENSED DIAZEPINONES, THEIR COMPOSITIONS AND METHODS OF USE AS PHARMACEUTICALS
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Disclosed are novel condensed diazepinones of formula I STR1 wherein B is a fused ring selected from STR2 X is--CH--or, when B is ortho-phenylene, X can also be nitrogen; A 1 is C 1-C. sub.2 alkylene; A 2 is C 1-C 2 when it is in the 2-position relative to the saturated heterocyclic ring nitrogen or a single bond or methylene when it is in the 3-or 4-position; R 1 is C 1-C 3 alkyl; R 2 is C. sub.1-C 7 alkyl, optionally hydroxy-substituted on at least one of its second to seventh carbon, or C 3-C 7 cycloalkyl, optionally hydroxy substituted, or C 3-C 7 cycloalkylmethyl; or R 1 and R 2 can, together with the nitrogen therebetween, be a 4-to 7-membered saturated monocyclic, heterocyclic ring which can optionally include an oxygen or N--CH 3 ; R 3 is hydrogen, chlorine, or methyl; R 4 is hydrogen or C 1-C 4 alkyl, R 5 is hydrogen, chlorine or C 1-C 4 alkyl; and Z is a single bond, oxygen, methylene or 1,2-ethylene; and NR 1 R 2--N oxides and nontoxic, pharmaceutically acceptable addition salts thereof. Also disclosed are pyrrolobenzodiazepinone intermediates, pharmaceutical compositions containing the condensed diazepinones and methods of using them to treat cardiovascular disorders, particularly bradycardia and bradyarrhythmia.
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