Key result
AJ-2615 is a novel Ca2+ entry blocker with built-in α1-adrenoceptor blocking activity that inhibits high K+-induced contractile response in rat aorta with an IC50 of 2.08 x 10-8 M.
Warrants preclinical development of this dual blocker; leaves open clinical translation without further evidence.
Summary: We studied the in vitro vascular relaxant properties of AJ-2615, (±)-/N-[6,11-dihydrodibenzo[b,e]-thiepin- 11-yl]-4-[4-fluorophenyl]-1-piperazinebutanamide monomaleate, a novel compound with long-lasting antihypertensive activity. AJ-2615 inhibited the high K + - induced contractile response in rat aorta with an IC50 of 2.08 x 10-8M. It was 13 times less potent than nifedipine and 3, 10, and 15 times more potent than verapamil, diltiazem, and fluanarizine, respectively. AJ-2615 also inhibited the high K +-induced 45Ca influx in rat aorta at almost the same concentration as that for inhibition of the contractile response. The inhibition of 45Ca 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 after AJ-2615 was removed from the medium. These results indicate that AJ-2615 acts directly on the potential-dependent Ca2 + channel in a long-lasting manner. AJ-2615 inhibited [3H]prazosin binding to dog aortic membranes (IC50=1.25 x 10-8M) and phenylephrine-induced contractile response in superior mesenteric artery (SMA) of rabbits (IC50=3.87 x 10-8M), indicating that AJ-2615 has potent α1-adrenoceptor blocking ctivity. AJ-2615 at 10-6M did not inhibit the caffeine-induced contractile response in rabbit SMA in Ca2 + -free medium, nor did it inhibit calmodulin (CAM) activity. It had little effect on prostaglandin F2α (PGF2α)- and 5-hydroxytryptamine (5-HT)- induced contractile response in SMA, and on bindings of other vasoactive substances tested to their receptors such as α2 β-and -adrenergic, 5-HT1- and 5-HT2-serotonergic, endothelin-1 (ET-1) and AT1-angiotensin II (All) receptors. We conclude that AJ-2615 is a Ca2+ entry blocker with α1-adrenoceptor blocking activity built-in in the molecule
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Okamura et al. (1993) studied this question. AJ-2615 vs. nifedipine, verapamil, diltiazem, and flunarizine was evaluated on Inhibition of high K+-induced contractile response in rat aorta. AJ-2615 is a novel Ca2+ entry blocker with built-in α1-adrenoceptor blocking activity that inhibits high K+-induced contractile response in rat aorta with an IC50 of 2.08 x 10-8 M.
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