Ligand-receptor interactions via hydrogen-bond formation. Synthesis and pharmacological evaluation of pyrrolo and pyrido analogues of the cardiotonic agent 7-hydroxycyclindole.
The syntheses of N,N-dimethyl-6,7,8,9-tetrahydro-3H,10H-pyrrolo[3,2-a] carbazol-7-amine (8), N,N-dimethyl-7,8,9,10-tetrahydro-11H-pyrido[3,2-a] carbazol-8-amine (9a), and the N,N,11-trimethyl analogue (9b) are described. The in vitro inotropic activity of these compounds, as well as the known cardiotonics amrinone and 7-hydroxycyclindole (7), was investigated. Compound 8, a pyrrolo analogue of 7, was devoid of inotropic activity, while the pyrido analogues 9 were equiactive to 7 and amrinone. These results suggest that the hydroxyl group of 7 functions as an H-bond acceptor, rather than a donor, and that on interaction of 7, and the pyrido analogues 9, with a common receptor, an orbital occupied by one of the oxygen lone pair electrons of 7 must assume the same orientation as the orbital occupied by the pyridine nitrogen lone pair.
D000631:Aminopyridines / Q000494:pharmacology; D000676:Amrinone; D000818:Animals; D002227:Carbazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002415:Cats; D006321:Heart / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D002227:Carbazoles; D002316:Cardiotonic Agents; C029513:7-hydroxycyclindole; D000676:Amrinone