Cowen P J, Green A R, Nutt D J
Nature. 1981 Mar 5;290(5801):54-5. doi: 10.1038/290054a0.
The mammalian central nervous system possesses specific high-affinity binding sites for the benzodiazepines and considerable evidence suggests that these binding sites are the pharmacological receptors through which these compounds act. Recently, ethyl beta-carboline-3-carboxylate (beta-CCE) has been identified in both human urine and rat brain. beta-CCE may be closely related to the endogenous ligand for the benzodiazepine receptor--it shows an affinity for the receptor of the same order as that of clonazepam, one of the most potent benzodiazepines, and is the first non-diazepinoid structure to be identified with an affinity in the nanomolar range. Furthermore, it is selective for the benzodiazepine receptor. Clinically and in animal studies, benzodiazepines have anti-convulsant, hypnotic and anxiolytic actions. We have therefore investigated whether beta-CCE exhibits any of these properties in rats. We report here that, in contrast to the benzodiazepines, beta-CCE lowers seizure threshold and reverses the sedative effect of flurazepam. If beta-CCE has a close structural relationship to the endogenous ligand, benzodiazepines may be antagonistic at the receptor site.
哺乳动物的中枢神经系统拥有苯二氮䓬类药物的特异性高亲和力结合位点，大量证据表明这些结合位点是这些化合物发挥作用的药理学受体。最近，在人类尿液和大鼠大脑中均发现了β-乙基咔啉-3-羧酸酯（β-CCE）。β-CCE可能与苯二氮䓬受体的内源性配体密切相关——它对该受体的亲和力与最有效的苯二氮䓬类药物之一氯硝西泮相当，并且是首个被鉴定出具有纳摩尔范围内亲和力的非二氮䓬类结构。此外，它对苯二氮䓬受体具有选择性。在临床和动物研究中，苯二氮䓬类药物具有抗惊厥、催眠和抗焦虑作用。因此，我们研究了β-CCE在大鼠中是否具有这些特性。我们在此报告，与苯二氮䓬类药物相反，β-CCE会降低癫痫发作阈值，并逆转氟西泮的镇静作用。如果β-CCE与内源性配体具有密切的结构关系，那么苯二氮䓬类药物可能在受体位点具有拮抗作用。
