Uchida W, Shibasaki K, Asano M, Takenaka T
Medicinal Research Laboratories II, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Arch Int Pharmacodyn Ther. 1993 Jan-Feb;321:30-40.
The pharmacological activities of YM-16151-1, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, and its optical isomers were investigated on the cardiovascular system of dogs anesthetized with pentobarbital. YM-16151-1 (0.1-1 mg/kg, i.v.) dose-dependently increased coronary arterial blood flow and decreased mean blood pressure, total peripheral resistance, heart rate and dp/dtmax with almost no effect on cardiac output. S-(-)- and R-(+)-isomers (0.1-1 mg/kg, i.v.) resembled YM-16151-1 in increasing coronary arterial blood flow and decreasing mean blood pressure and total peripheral resistance and were almost equipotent with YM-16151-1 in these effects. However, these optical isomers differed from YM-16151-1 in the changes in heart rate, dp/dtmax and cardiac output. The rank order of potency for these cardiac effects was S-(-)-YM-16151-1 > YM-16151-1 > R-(+)-YM-16151-1. In vagotomized dogs, YM-16151-1 inhibited the isoproterenol (0.2 microgram/kg, i.v.)-induced tachycardia with an ED50 value of 0.11 mg/kg, i.v. S-(-)- and R-(+)-isomers also inhibited the isoproterenol-induced tachycardia with ED50 values of 0.039 and 0.39 mg/kg, i.v., respectively. Thus, the difference in cardiac effects obtained from the anesthetized dog study among these compounds may be caused by the potency difference of their beta 1-adrenoceptor blocking activities. In addition, R-(+)-isomer, possessing a less potent beta 1-adrenoceptor blocking activity than S-(-)-isomer, only produced a dose-dependent tachycardia at the hypotensive doses in conscious dogs. The present results demonstrate that YM-16151-1 behaves as a hybrid compound combining calcium entry blocking and beta 1-adrenoceptor blocking activities, and also demonstrate that YM-16151-1 is a racemic mixture with equal proportions of the two optical isomers, and, as such, the overall activity may be due to the sum of the activities of the individual optical isomers.
研究了兼具钙通道阻滞和β1 -肾上腺素能受体阻滞作用的YM - 16151 - 1及其光学异构体对戊巴比妥麻醉犬心血管系统的药理活性。静脉注射YM - 16151 - 1（0.1 - 1mg/kg）可剂量依赖性增加冠状动脉血流量，并降低平均血压、总外周阻力、心率和dp/dtmax，对心输出量几乎无影响。S - (-)-和R - (+)-异构体（0.1 - 1mg/kg，静脉注射）在增加冠状动脉血流量、降低平均血压和总外周阻力方面与YM - 16151 - 1相似，且在这些作用上与YM - 16151 - 1几乎等效。然而，这些光学异构体在心率、dp/dtmax和心输出量的变化方面与YM - 16151 - 1不同。这些心脏效应的效价顺序为S - (-)-YM - 16151 - 1 > YM - 16151 - 1 > R - (+)-YM - 16151 - 1。在迷走神经切断的犬中，YM - 16151 - 1抑制异丙肾上腺素（0.2μg/kg，静脉注射）诱导的心动过速，静脉注射ED50值为0.11mg/kg。S - (-)-和R - (+)-异构体也抑制异丙肾上腺素诱导的心动过速，静脉注射ED50值分别为0.039和0.39mg/kg。因此，在麻醉犬研究中这些化合物心脏效应的差异可能是由它们β1 -肾上腺素能受体阻滞活性的效价差异引起的。此外，R - (+)-异构体的β1 -肾上腺素能受体阻滞活性比S - (-)-异构体弱，在清醒犬的降压剂量下仅产生剂量依赖性心动过速。目前的结果表明YM - 16151 - 1表现为一种兼具钙通道阻滞和β1 -肾上腺素能受体阻滞活性的混合化合物，也表明YM - 16151 - 1是两种光学异构体比例相等的外消旋混合物，因此，总体活性可能是由于各个光学异构体活性的总和。
