PHARMACOLOGICAL PROPERTIES OF A NOVEL CA(2-2615, IN-VITRO() ENTRY BLOCKER, AJ)

We studied the in vitro vascular relaxant properties of AJ-2615, n-11- yl]-4-[4-fluorophenyl]-1-piperazinebutanamide monomaleate, a novel com pound with long-lasting antihypertensive activity. AJ-2615 inhibited t he high K+induced contractile response in rat aorta with an IC50 of 2. 08 x 10(-8)M. It was 13 times less potent than nifedipine and 3, 10, a nd 15 times more potent than verapamil, diltiazem, and fluanarizine, r espectively. AJ-2615 also inhibited the high K+-induced Ca-45 influx i n rat aorta at almost the same concentration as that for inhibition of the contractile response. The inhibition of Ca-45 influx was reversed by Bay k 8644, a Ca2+ channel agonist. The effects of AJ-2615 on the contractile response and Ca2+ influx persisted for at least 120 min af ter AJ-2615 was removed from the medium. These results indicate that A J-2615 acts directly on the potential-dependent Ca2+ channel in a long -lasting manner. AJ-2615 inhibited [H-3]prazosin binding to dog aortic membranes (IC50 = 1.25 x 10(-8)M) and phenylephrine-induced contracti le response in superior mesenteric artery (SMA) of rabbits (IC50 = 3.8 7 x 10(-8)M), indicating that AJ-2615 has potent alpha1-adrenoceptor b locking activity. AJ-2615 at 10(-6)M did not inhibit the caffeine-indu ced contractile response in rabbit SMA in Ca2+-free medium, nor did it inhibit calmodulin (CAM) activity. It had little effect on prostaglan din F2alpha (PGF2alpha)- and 5-hydroxytryptamine (5-HT)-induced contra ctile response in SMA, and on bindings of other vasoactive substances tested to their receptors such as alpha2- and beta-adrenergic, 5-HT1- and 5-HT2-serotonergic, endothelin-1 (ET-1) and AT1-angiotensin II (AI I) receptors. We conclude that AJ-2615 is a Ca2+ entry blocker with al pha2-adrenoceptor blocking activity built-in in the molecule.