Tricyclic Compounds as Selective Muscarinic Receptor Antagonists. 3. Structure-Selectivity Relationships in a Series of Cardioselective (M2) Antimuscarinics

Article abstract of DOI:10.1021/jm00128a008

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.