Chiesi M, Schwaller R, Eichenberger K
Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
Biochem Pharmacol. 1988 Nov 15;37(22):4399-403. doi: 10.1016/0006-2952(88)90623-5.
Na+-induced Ca2+-release from guinea-pig heart mitochondria is inhibited by benzodiazepines such as clonazepam (compound II, IC50: 12 microM). The capacity of various related compounds to inhibit the rapid Ca2+-efflux induced by 20 mM Na+ was examined. The potency of inhibition was found to depend on several factors, such as a 2'-halogen substitution and the presence of a secondary amido group. Very effective inhibitors were identified among the triazolo derivatives of benzodiazepines or obtained by replacing the diazepine ring by an oxazepine or a thiazepine. Some of these favourable structural modifications were compounded in the benzothiazepine 7-chloro-3,5-dihydro-5-phenyl-1H-4,1-benzothiazepine-2-on (compound XVI), which proved to be about 20 times more potent than the related compounds clonazepam and diltiazem. Compound XVI, which has an IC50 in the submicromolar range, is the most potent selective inhibitor of the mitochondrial exchanger so far reported. The structural requirements found for the inhibition of the mitochondrial Na+-Ca2+ exchanger were quite distinct from those described for the binding of benzodiazepines to their central-type and peripheral-type sites.
苯二氮䓬类药物如氯硝西泮（化合物II，IC50：12微摩尔）可抑制豚鼠心脏线粒体中钠离子诱导的钙离子释放。研究了各种相关化合物抑制20毫摩尔钠离子诱导的快速钙离子外流的能力。发现抑制效力取决于几个因素，如2'-卤素取代和仲酰胺基的存在。在苯二氮䓬类药物的三唑衍生物中或通过用恶唑并氮杂䓬或噻唑并氮杂䓬取代二氮杂䓬环鉴定出了非常有效的抑制剂。其中一些有利的结构修饰结合在了苯并噻氮䓬7-氯-3,5-二氢-5-苯基-1H-4,1-苯并噻氮䓬-2-酮（化合物XVI）中，事实证明其效力比相关化合物氯硝西泮和地尔硫䓬强约20倍。化合物XVI的IC50在亚微摩尔范围内，是迄今为止报道的最有效的线粒体交换体选择性抑制剂。发现的抑制线粒体钠离子-钙离子交换体的结构要求与描述的苯二氮䓬类药物与其中枢型和外周型位点结合的结构要求截然不同。
