URINARY AND BRAIN BETA-CARBOLINE-3-CARBOXYLATES AS POTENT INHIBITORS OF BRAIN BENZODIAZEPINE RECEPTORS
URINARY AND BRAIN BETA-CARBOLINE-3-CARBOXYLATES AS POTENT INHIBITORS OF BRAIN BENZODIAZEPINE RECEPTORS
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DOI：
10.1073/pnas.77.4.2288
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发表时间：
1980-01-01
期刊：
影响因子：
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通讯作者：
OLSEN, CE
中科院分区：
文献类型：
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作者：
BRAESTRUP, C;NIELSEN, M;OLSEN, CE
苯二氮卓类药物可能通过与脑特异性高亲和力苯二氮卓类受体相互作用而发挥其抗焦虑、催眠和抗惊厥作用。在寻找这些受体的可能的内源性配体时，我们通过提取、热乙醇处理和柱层析从人尿中纯化了107倍的化合物。该化合物被鉴定为β-咔啉-3-羧酸乙酯（IIc）通过质谱法，NMR光谱法，和合成; IIc也从脑组织中分离（20纳克/克）通过类似的程序。非常小浓度的IIc将[3 H]地西泮完全从特异性脑受体置换，但不从肝和肾结合位点置换;与apx相比，引起特异性[3 H]地西泮结合的50%抑制的浓度为4-7 nM。5 nM的强效苯二氮卓类劳拉西泮。奎宁环二苯乙酸酯，纳洛酮，螺哌啶，血清素，蝇蕈醇和WB 4101的特异性结合位点不受IIc的影响。与苯二氮卓类药物相反，IIc对前脑苯二氮卓类受体表现出混合型竞争性抑制（负协同性）。苯并二氮杂受体的内源性配体可以是β-苯并二氮杂受体的衍生物。咔啉-3-羧酸
Benzodiazepines probably exert their anxiolytic, hypnotic and anticonvulsant effects by interacting with brain-specific high-affinity benzodiazepine receptors. In searching for possible endogenous ligands for these receptors, we have purified a compound 107-fold from human urine by extractions, treatment with hot ethanol and column chromatography. The compound was identified as .beta.-carboline-3-carboxylic acid ethyl ester (IIc) by mass spectrometry, NMR spectrometry, and synthesis; IIc was also isolated from brain tissues (20 ng/g) by similar procedures. Very small concentration of IIc displaced [3H]diazepam completely from specific cerebral receptors, but not from liver and kidney binding sites; the concentration causing 50% inhibition of specific [3H]diazepam binding was 4-7 nM compared to .apprx. 5 nM for the potent benzodiazepine lorazepam. Specific binding sites for quinuclidinyl benzilate, naloxone, spiroperidol, serotonin, muscimol and WB 4101 were not affected by IIc. In contrast to benzodiazepines, IIc exhibits mixed type competitive inhibition of forebrain benzodiazepine receptors (negative cooperativity). An endogenous ligand for benzodiazepine receptors may be a derivative of .beta.-carboline-3-carboxylic acid.