Pereira E F, Aracava Y, Aronstam R S, Barreiro E J, Albuquerque E X
Laboratory of Molecular Pharmacology II, Institute of Biophysics "Carlos Chagas Filho", Federal University of Rio de Janeiro, Brazil.
J Pharmacol Exp Ther. 1992 Apr;261(1):331-40.
Electrophysiological and biochemical studies demonstrated that pyrazole, an inhibitor of alcohol dehydrogenase and a proposed therapeutic agent for treatment of alcoholic intoxication, activated and blocked the N-methyl-D-aspartate (NMDA) receptor and did not interact significantly with the end-plate nicotinic acetylcholine receptor (AChR). Pyrazole, at concentrations as low as 0.5 microM, applied to outside-out patches excised from the membrane of cultured rat hippocampal neurons, elicited single-channel currents of 48 pS which were blocked by DL-2-amino-5-phosphorovaleric acid, a competitive antagonist of NMDA. In addition, binding studies showed that pyrazole displaced 1-(cis-2-carboxypiperidine-4-yl)methyl-1-phosphoric acid from the agonist recognition site of the NMDA receptor in a concentration-dependent manner and enhanced the binding of (+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine to this complex. These data indicate that pyrazole is an agonist at NMDA receptors. However, at higher concentrations, open and burst times as well as the frequency of single-channel currents activated by pyrazole were reduced significantly, a finding which suggests that this compound is also an open channel blocker. In agreement with these results, it was shown biochemically that pyrazole was able to stimulate influx of Ca++ into rat brain microsomes via NMDA receptors and on the other hand to block the influx of Ca++ induced by NMDA. Pyrazole was unable to affect the neuromuscular transmission of frog sartorius muscle-sciatic nerve preparations. Additionally, pyrazole did not interact either with the agonist recognition site or with noncompetitive sites of the AChR. However, this drug had a very weak agonist-like action on the AChR of the Torpedo electric organ, most likely via binding sites different from those described previously for acetylcholine. Therefore, the therapeutic efficacy of pyrazole may be related at least in part to its effects on the NMDA receptor. Furthermore, this compound, because of the small size and rigidity of its molecular structure, becomes a promising drug for the study of the NMDA receptor. Indeed its use may allow a better understanding of the physiological and pathological processes involving this receptor.
电生理学和生物化学研究表明，吡唑作为乙醇脱氢酶的抑制剂以及一种用于治疗酒精中毒的潜在治疗药物，可激活并阻断N-甲基-D-天冬氨酸（NMDA）受体，且与终板烟碱型乙酰胆碱受体（AChR）无明显相互作用。吡唑在低至0.5微摩尔浓度时，作用于从培养的大鼠海马神经元膜上切下的外向膜片，可引发48皮西门子的单通道电流，该电流可被NMDA的竞争性拮抗剂DL-2-氨基-5-磷酸戊酸阻断。此外，结合研究表明，吡唑以浓度依赖的方式从NMDA受体的激动剂识别位点取代1-(顺式-2-羧基哌啶-4-基)甲基-1-磷酸，并增强(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺与该复合物的结合。这些数据表明吡唑是NMDA受体的激动剂。然而，在较高浓度时，吡唑激活的单通道电流的开放时间、爆发时间以及频率均显著降低，这一发现表明该化合物也是一种开放通道阻滞剂。与这些结果一致，生化研究表明吡唑能够通过NMDA受体刺激钙离子流入大鼠脑微粒体，另一方面又能阻断由NMDA诱导的钙离子流入。吡唑无法影响青蛙缝匠肌-坐骨神经标本的神经肌肉传递。此外，吡唑既不与AChR的激动剂识别位点相互作用，也不与非竞争性位点相互作用。然而，这种药物对电鳐电器官的AChR具有非常微弱的类似激动剂的作用，最有可能是通过与先前描述的乙酰胆碱不同的结合位点。因此，吡唑的治疗效果可能至少部分与其对NMDA受体的作用有关。此外，由于其分子结构的小尺寸和刚性，该化合物成为研究NMDA受体的一种有前景的药物。实际上，它的使用可能有助于更好地理解涉及该受体的生理和病理过程。
