Moore J B, Miller W C, Mockoviak S
R.W. Johnson Pharmaceutical Research Institute, Department of Experimental Therapeutics, Raritan, NJ 08869.
Agents Actions. 1993 Sep;40(1-2):57-61. doi: 10.1007/BF01976752.
RWJ-22108 is a novel calcium entry blocker that has potential therapeutic use as an antiasthmatic agent. Although displaying typical potent inhibition of 45Ca uptake into aortic rings (IC50 = 7.1 nM) and displacement of [3H]nitrendipine from cardiac membranes (IC50 = 137 nM), RWJ-22108 demonstrates tissue selectivity in the inhibition of KCl-induced contractions. RWJ-22108 inhibits the calcium-dependent contraction of canine bronchiolar smooth muscle with an IC50 of 5.7 nM. The IC50 femoral artery/IC50 bronchiolar ratios are 2.85, 8.02, 1.47 and 1.96 for nifedipine, RWJ-22108, verapamil, and gallopamil, respectively. Furthermore, this selectivity ratio (range 2.8-5.5) of RWJ-22108 is also observed when inhibition of other pulmonary and cardiovascular smooth muscles are compared. Using canine tracheal muscle and rabbit aortae, the IC50 aorta/IC50 trachea ratio is 1.75 for RWJ-22108 compared to approximately 0.5 for several calcium blocker standards. These results indicate that in vitro RWJ-22108 is a bronchoselective calcium channel blocker.
RWJ - 22108是一种新型的钙通道阻滞剂，具有作为抗哮喘药物的潜在治疗用途。尽管RWJ - 22108对主动脉环摄取45Ca表现出典型的强效抑制作用（IC50 = 7.1 nM），并能从心肌膜上置换出[3H]尼群地平（IC50 = 137 nM），但它在抑制氯化钾诱导的收缩方面表现出组织选择性。RWJ - 22108抑制犬细支气管平滑肌的钙依赖性收缩，IC50为5.7 nM。硝苯地平、RWJ - 22108、维拉帕米和加洛帕米的股动脉IC50/细支气管IC50比值分别为2.85、8.02、1.47和1.96。此外，当比较对其他肺和心血管平滑肌的抑制作用时，也观察到RWJ - 22108的这种选择性比值（范围为2.8 - 5.5）。以犬气管平滑肌和兔主动脉为例，RWJ - 22108的主动脉IC50/气管IC50比值为1.75，而几种钙通道阻滞剂标准品的该比值约为0.5。这些结果表明，在体外，RWJ - 22108是一种支气管选择性钙通道阻滞剂。
