Unusual interactions of benzodiazepine receptor antagonists
Unusual interactions of benzodiazepine receptor antagonists
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苯二氮卓受体拮抗剂的异常相互作用
作者：
D. Nutt;P. Cowen;H. Little
最近已经描述了两种化合物，其在体内作为有效的苯并二氮杂（BDZ）拮抗剂，并且在体外对哺乳动物中枢神经系统（CNS）的BDZ受体显示出高亲和力和选择性。一种是从人尿液中提取的β-咔啉-3-羧酸乙酯（β-CCE），可能与BDZ受体的内源性配体有关1 -3。它逆转BDZ在体内的作用4，5和体外6，但也具有内在活性，因为它降低了对γ-氨基丁酸（GABA）作用具有拮抗作用的药物的癫痫发作阈值5，7。另一种化合物，咪唑二氮杂卓（Ro 15-1788），也是体内和体外BDZ结合的有效和特异性拮抗剂8，可阻断常规BDZ的镇静、催眠和抗惊厥作用，但未显示任何内在活性9，10。由于这两种BDZ“拮抗剂”的作用不同，我们在这里研究了它们在两个完善的系统中的相互作用，用于评估BDZ活性：体内癫痫发作阈值11和GABA对颈交感神经节的作用12。我们发现Ro 15-1788不仅对抗BDZ的作用，而且在两个系统中都是β-CCE的有效拮抗剂。在高剂量下，它具有BDZ样活性，表明它可能是BDZ受体位点的部分激动剂。
Two compounds have recently been described which act as potent benzodiazepine (BDZ) antagonists in vivo and which, in vitro, show high affinity and selectivity for the BDZ receptor of the mammalian central nervous system (CNS). One, ethyl β-carboline-3-carboxylate (β-CCE), was extracted from human urine and may be related to an endogenous ligand for the BDZ receptor1–3. It reverses the effects of BDZs in vivo4,5 and in vitro6, but also has intrinsic activity, as it lowers the seizure threshold to drugs antagonistic to the action of γ-aminobutyric acid (GABA)5,7. The other compound, an imidazodiazepine (Ro 15-1788), which is also a potent and specific antagonist of BDZ binding in vivo and in vitro8, blocked the sedative, hypnotic and anticonvulsant actions of conventional BDZs, without demonstrating any intrinsic activity9,10. Because of the different profiles of action of these two BDZ ‘antagonists’, we have here investigated their interactions in two well established systems for assessing BDZ activity: seizure thresholds in vivo11 and the action of GABA on cervical sympathetic ganglia in vitro12. We find that Ro 15-1788 not only opposes the actions of BDZs but also is an effective antagonist of β-CCE in both systems. At high doses it has BDZ-like activity, suggesting that it may be a partial agonist at the BDZ receptor site.