Mikio Kurokawa

Pharmacologic properties of a novel Ca2+ entry blocker, AJ-2615, in vitro

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 10-8 M. 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 10-8 M) and phenylephrine-induced contractile response in superior mesenteric artery (SMA) of rabbits (IC50=3.87 x 10-8 M), indicating that AJ-2615 has potent α1-adrenoceptor blocking ctivity. AJ-2615 at 10-6 M 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

Inhibitory effect of the new calcium antagonist AJ-2615 on progression of atherosclerosis in cholesterol-fed rabbits.

The effects of a new calcium antagonist, AJ-2615, on progression of atherosclerosis were investigated in rabbits fed a diet high in cholesterol and compared with those of prazosin, diltiazem, and their combination. In the AJ-2615 (30 mg/kg p.o. once daily) group, high cholesterol diet-induced increases in plasma concentrations of total cholesterol, free cholesterol, and phospholipid were significantly decreased. In addition, increases in aortic lipids and calcium content, as well as those in the atherosclerotic lesion area were clearly reduced by AJ-2615. On the other hand, prazosin (3 mg/kg p.o. twice daily) and diltiazem (50 mg/kg p.o. twice daily) groups displayed no such inhibitory effects. However, the group receiving the combination of prazosin and diltiazem at their respective dose levels exhibited a significant reduction in the increase in calcium content of the aorta and a slight decrease in the atherosclerotic lesion area, although there was no decrease in plasma or aortic lipid content. These results suggest that in addition to its calcium antagonistic and alpha 1-adrenoceptor blocking actions, some other yet-unidentified properties of AJ-2615 might contribute to the antiatherosclerotic effect of this agent.