title: Pharmacologic properties of a novel Ca2+ entry blocker, AJ-2615, in vitro.
abstract: 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 alpha 1-adrenoceptor blocking activity. AJ-2615 at 10(-6) M did not inhibit the caffeine-induced contractile response in rabbit SMA in Ca(2+)-free medium, nor did it inhibit calmodulin (CAM) activity.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Dainippon Pharmaceutical, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: B
authors.initials: B
authors.lastname: Fujitani
authors.forename: K
authors.initials: K
authors.lastname: Furukawa
authors.forename: T
authors.initials: T
authors.lastname: Une
authors.forename: T
authors.initials: T
authors.lastname: Nukuda
authors.forename: M
authors.initials: M
authors.lastname: Komiya
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D003988:Dibenzothiepins / Q000494:pharmacology*; D004285:Dogs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D002147:Calmodulin; D003988:Dibenzothiepins; D010879:Piperazines; D011942:Receptors, Adrenergic, alpha; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C067818:monatepil; D011188:Potassium; D002118:Calcium