Electrophysiologic activity and antiarrhythmic efficacy of CK-3579, a new class III antiarrhythmic agent with beta-adrenergic blocking properties.
CK-3579 (N-[4-[2-hydroxy-3-[[2-[4-(1H-inidazol-1- yl)phenoxy]ethyl]amino]propoxy]phenyl]methanesulfonamide, HCL-[RS]), is a new class III antiarrhythmic agent with beta-adrenoceptor blocking properties shown to be effective in preventing ventricular arrhythmias in experimental animals. We examined the beta 1- and beta 2-adrenoceptor binding properties, cellular electrophysiology, and antiarrhythmic efficacy of CK-3579 and the two enantiomers CK-4000 (S) and CK-4001 (R). Both CK-3579 and CK-4000 were equipotent in displacing [3H]dihydroalprenolol from cardiac membranes (IC50 = 2.4 +/- 0.3 and 1.7 +/- 0.4 microM, respectively) and were approximately 23-59 times more selective for the heart receptor than the lung receptor. The IC50 for CK-4001 at the beta 1-adrenoceptor was 38.1 +/- 8 microM and > 100 microM at the beta 2-adrenoceptor. In isolated canine Purkinje fibers and ventricular muscle preparations, all three compounds increased action potential duration at 95% repolarization (APD95) with equal potency, having an average EC20 of approximately 1 microM in Purkinje fiber and 2 microM in ventricular muscle. No significant effects were observed on any other action potential (AP) parameters. In Purkinje fibers with APs shortened by isoproterenol, the class III activity of CK-4000 was significantly greater than that of CK-4001. CK-4000 inhibits the potassium delayed rectifier current Ik in a concentration-dependent manner in isolated feline ventricular myocytes. The IC50 for inhibition of fully activated current was 0.4 +/- 0.2 microM. Steady-state currents negative to -20 mV were unchanged by CK-4000, but the "hump" in the outward current between -20 and +30 mV was flattened.(ABSTRACT TRUNCATED AT 250 WORDS)
Argentieri
T M
TM
Department of Biological Research, Berlex Laboratories, Cedar Knolls, New Jersey.
Troy
H H
HH
Carroll
M S
MS
Doroshuk
C M
CM
Sullivan
M E
ME
D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D002415:Cats; D004285:Dogs; D004558:Electric Stimulation; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008955:Models, Cardiovascular; D011412:Propanolamines / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C063532:ersentilide