title: Pharmacological profiles of YM-16151-1 and its optical isomers: a novel calcium entry blocking and selective beta-1 adrenoceptor blocking agent.
abstract: The pharmacological properties of YM-16151-1 [(+/-)-dimethyl 4-[2-[4-(2-hydroxy-3-phenoxypropylamino)butoxyl]-5-nitrop hen yl]-2,6- dimethyl-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride] and its optical isomers were evaluated in in vitro studies and radioligand binding assay. In isolated tissues, YM-16151-1 produced a competitive antagonism of CaCl2-induced contraction in the isolated rabbit aorta with a pKca-1 value of 8.17, and also produced a competitive antagonism of isoproterenol-induced positive chronotropic responses in the isolated rat atria with a pA2 value of 8.47. In rat brain membrane preparations, YM-16151-1 produced dose-dependent inhibitions of [3H]nitrendipine and [3H]dihydroalprenolol bindings with pKi values of 7.21 and 8.07, respectively. Calcium entry blocking activity of YM-16151-1 was 7 times weaker and 3 times greater than nifedipine and diltiazem, respectively. Beta-1 adrenoceptor blocking activity of YM-16151-1 was 2 times weaker than that of propranolol. YM-16151-1 showed about 900-fold selectivity for beta-1 adrenoceptor. YM-16151-1 also showed a weak alpha-1 adrenoceptor blocking activity and its potency was about 13 times weaker than that of phentolamine. S-(-)- and R-(+)-isomers of YM-16151-1 showed the same potency of calcium entry blocking activity. However, in beta-1 adrenoceptor blocking activity, the S-(-)-enantiomer was about 13 to 22 times more potent than the R-(+)-enantiomer. Oral administration of YM-16151-1 produced a dose-dependent blood pressure lowering effect without increasing heart rate in conscious spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.forename: W
authors.initials: W
authors.lastname: Uchida
authors.forename: K
authors.initials: K
authors.lastname: Shibasaki
authors.forename: M
authors.initials: M
authors.lastname: Terai
authors.forename: O
authors.initials: O
authors.lastname: Inagaki
authors.forename: T
authors.initials: T
authors.lastname: Takenaka
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: T
authors.initials: T
authors.lastname: Fujikura
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009568:Nitrendipine / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009596:Nitrophenols; C064876:YM 16151-1; D009568:Nitrendipine