Studies on diazepam-insensitive benzodiazepine receptors

为了表征对二氮卓类药物不敏感的苯二氮卓类受体，研究了各种咪唑苯二氮卓类化合物对[^3H] Ro 15-4513结合和乙醇诱导的抗惊厥活性的影响。在过量地西泮存在的情况下，[^3H] Ro 15-4513结合的Scatchard分析显示，在大鼠脑和培养的小脑颗粒细胞中，[^3H] Ro 15-4513结合呈线性。尽管一些咪唑并苯并二氮杂卓类化合物如氟马西尼（Ro 15-1788）和Ro 19-4603以及吡唑并喹啉化合物CGS 8216对二氮杂卓不敏感位点显示出高亲和力，但经典的苯并二氮杂卓类和β-咔啉类似物如甲基-6，7-二甲基-4-乙基-β-咔啉-3-羧酸酯（DMCM）和FG 7142不能取代这种结合。用戊四唑（60 mg/kg，i. p.）在小鼠给药后2 ~ 3 min内出现慢性癫痫发作，乙醇（1.5g/kg）可抑制这种作用。Ro 15-4513（4 mg/kg）和Ro 19-4603（4 mg/kg）可拮抗乙醇的抗惊厥作用。但这些化合物对苯巴比妥（50 mg/kg）的抗惊厥作用无拮抗作用。这些结果表明，对二氮杂不敏感的苯二氮杂受体对咪唑并苯二氮杂化合物如Ro 15-4513和Ro 19-4603具有高亲和力，并且该受体在这些咪唑并苯二氮杂化合物逆转乙醇的急性作用中起重要作用。

In order to characterize diazepam-insensitive benzodiazepine receptors, effects of various imidazobenzodiazepine compounds on [^3H] Ro 15-4513 binding and ethanolinduced anticonvulsant activity were investigated. Scatchard analysis of [^3H] Ro 15-4513 binding in the presence of excess amount of diazepam revealed linear plots in rat brain and cultured cerebellar granule cells. Although some imidazobenzodiazepine compounds such as flumazenil (Ro 15-1788) and Ro 19-4603, and a pyrazoloquinoline compound, CGS 8216, showed high affinity for the diazepam-insensitive sites, classical benzodiazepines and beta-carboline analogues such as methyl-6,7-dimethyl-4-ethyl-beta-carboline-3-carboxylate (DMCM) and FG 7142 did not displace the binding. Treatment of mice with pentylenetetrazole (60mg/kg, i.p.) exhibited chronic seizures within 2 to 3 min after administration in mice and this effect was suppressed by ethanol (1.5g/kg) . Ro 15-4513 (4mg/kg) and Ro 19-4603 (4mg/kg) antagonized the anticonvulsant action of ethanol. However, these compounds showed weak antagonistic effects on anticonvulsant activity of phenobarbital (50mg/kg) . These results suggest that diazepm-insensitive benzodiazepine receptors have high affinity for imidazobenzodiazepine compounds such as Ro 15-4513 and Ro 19-4603 and that the receptors play an important role in reversal of acute effects of ethanol by these imidazobenzodiazepine compounds.