Chatelain P, Beaufort P, Meysmans L, Clinet M
Sanofi-Labaz Research Centre, Brussels, Belgium.
Mol Pharmacol. 1991 Jan;39(1):64-71.
SR 33557 represents a new class of compounds (indolizine sulfone) that inhibit L-type Ca2+ channels. [3H]SR 33557 has been shown to bind with high affinity (Kd congruent to 0.36 nM, calculated from saturation isotherms and association/dissociation kinetics) to a single class of sites in a purified preparation of rat cardiac sarcolemmal membranes. The binding was found to be saturable and reversible. The maximal binding capacity was in approximately 1:1 stoichiometry with that of other Ca2+ channel antagonists. Various divalent cations (Mg2+, Mn2+, Ca2+, Ba2+, and Cd2+) were shown to inhibit specific [3H]SR 33557 binding, with Cd2+ being the most potent. Among several receptor or channel ligands (including omega-conotoxin and Na+ and K+ channel modulators), only the L-type Ca2+ channel antagonists were found to displace [3H]SR 33557. However, dihydropyridines, phenylalkylamines, benzothiazepines, and diphenylbutylpiperidines were found to inhibit [3H]SR 33557 in a noncompetitive manner as demonstrated by displacement and saturation experiments in addition to dissociation kinetics. From these results, we suggest that SR 33557 binds with high affinity to a unique site on the L-type Ca2+ channel found in rat cardiac sarcolemmal membranes.
SR 33557代表一类新型化合物（中氮茚砜），可抑制L型Ca2+通道。[3H]SR 33557已被证明能以高亲和力（根据饱和等温线和结合/解离动力学计算，Kd约为0.36 nM）与纯化的大鼠心肌肌膜制备物中的一类单一位点结合。发现这种结合是可饱和且可逆的。最大结合容量与其他Ca2+通道拮抗剂的化学计量比约为1:1。各种二价阳离子（Mg2+、Mn2+、Ca2+、Ba2+和Cd2+）均显示可抑制特异性[3H]SR 33557结合，其中Cd2+最为有效。在几种受体或通道配体（包括ω-芋螺毒素以及Na+和K+通道调节剂）中，仅发现L型Ca2+通道拮抗剂能取代[3H]SR 33557。然而，除解离动力学外，通过取代和饱和实验表明，二氢吡啶类、苯烷基胺类、苯并硫氮杂䓬类和二苯基丁基哌啶类以非竞争性方式抑制[3H]SR 33557。根据这些结果，我们认为SR 33557以高亲和力与大鼠心肌肌膜中发现的L型Ca2+通道上的一个独特位点结合。
