Tricyclic compounds as selective muscarinic receptor antagonists. 3. Structure-selectivity relationships in a series of cardioselective (M2) antimuscarinics

• Published in: Journal of medicinal chemistry Vol. 32; no. 8; pp. 1718 - 1724
• Main Authors: Engel, Wolfhard W, Eberlein, Wolfgang G, Mihm, Gerhard, Hammer, Rudolf, Trummlitz, Guenter
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.08.1989
• Subjects: acetylcholine; Animals; Chemical Phenomena; Chemistry; In Vitro Techniques; Myocardium - metabolism; Parasympatholytics - chemical synthesis; Parasympatholytics - metabolism; Pirenzepine - analogs & derivatives; Pirenzepine - chemical synthesis; Pirenzepine - metabolism; Pirenzepine - pharmacology; Rats; Receptors, Muscarinic - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• 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 spatial 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.