Imidazopyridines: roles of pyridine nitrogen position and methylsulfinyl oxygen for in vitro positive inotropic mechanism and chronotropic activity.
The role of structural features of sulmazole, an imidazo(4,5-b)pyridine, in its inotropic action was examined by comparison with its reduced (4-methylthiophenyl) analog EMD 46512 and the corresponding imidazo(4,5-c)pyridine isomers isomazole and EMD 41000 on isolated guinea-pig papillary muscles and right atria and on Na,K-ATPase and phosphodiesterase III isolated from guinea-pig hearts. The pyridine nitrogen position in sulmazole was crucial for affinity to Na,K-ATPase (IC50 = 350 microM) because the imidazo(4,5-c)pyridines had little effect. Participation of Na,K-ATPase inhibition in sulmazole's inotropic effect (EC50 = 180 microM) was suggested by synergism with the Na channel activator germitrine. The methylsulfinyl oxygen at the phenyl ring decreased the affinity to Na,K-ATPase of sulmazole 40-fold: The reduced analog EMD 46512 was a potent inhibitor of Na,K-ATPase (IC50 = 8.5 microM) and a more potent inotropic agent (EC50 = 8.2 microM) that appeared to act predominantly through Na,K-ATPase inhibition. Micromolar through Na,K-ATPase inhibition. Micromolar IC50s for inhibition of phosphodiesterase III were 49 (sulmazole), 34 (EMD 46512), 18 (isomazole), and 13 (EMD 41000). Participation of this mechanism in the inotropic effect of sulmazole, isomazole, and EMD 41000, but not EMD 46512, was indicated by augmentation of slow action potentials, synergism with histamine, inhibition by carbachol, and (with the exception of EMD 41000) a positive chronotropic effect on the right atrium. Sulmazole appeared to combine the actions of its 4-methylthiophenyl analog EMD 46512 (an inhibitor of Na,K-ATPase) and of its imidazo(4,5-c)pyridine isomer isomazole (an inhibitor of phosphodiesterase III).
Honerjäger
P
P
Institut für Pharmakologie und Toxikologie, Technischen Universität München, F.R.G.
Klockow
M
M
Schönsteiner
G
G
Jonas
R
R
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D006632:Histamine / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008968:Molecular Conformation; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D007093:Imidazoles; D006632:Histamine; D002217:Carbachol; D012964:Sodium; D010727:Phosphoric Diester Hydrolases; D000254:Sodium-Potassium-Exchanging ATPase; C029758:sulmazole