Pharmacological properties of YM-15430-1, a 1,4-dihydropyridine derivative with beta 1-adrenoceptor-blocking activity.
The pharmacological properties of YM-15430-1 and its stereoisomers (YM-15430-2, YM-15430-3 and YM-15430-4) were evaluated in in vitro experiments. In the rabbit isolated aorta, all compounds antagonized the CaCl2-induced contraction with a negative logarithm of the dissociation constant in calcium antagonism of 8.51, 7.13, 8.68 and 7.16, respectively. In the rat isolated right atrium, YM-15430-1 produced a competitive antagonism of the isoprenaline-induced tachycardia with a pA2 value of 7.59. YM-15430-2, YM-15430-3 and YM-15430-4 also antagonized the isoprenaline-induced tachycardia, with pA2 values of 7.91, 7.09 and 6.24, respectively. Because it was the most active of the 4 stereoisomers, YM-15430-1 was particularly studied. YM-15430-1 showed an about 100-fold greater selectivity for beta 1- than for beta 2-adrenoceptors, and had no intrinsic sympathomimetic activity. These results suggest that YM-15430-1 is a hybrid compound which combines calcium entry-blocking and selective beta 1-adrenoceptor-blocking activities in one molecule.
Shibasaki
K
K
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Uchida
W
W
Shirai
Y
Y
Inagaki
O
O
Asano
M
M
Takenaka
T
T
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D050198:Phenoxypropanolamines; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013610:Tachycardia / Q000139:chemically induced; D014661:Vasoconstriction / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D050198:Phenoxypropanolamines; C092967:YM 15430-1; D007545:Isoproterenol