Ramoa A S, Albuquerque E X
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
FEBS Lett. 1988 Aug 1;235(1-2):156-62. doi: 10.1016/0014-5793(88)81254-7.
Phencyclidine (PCP) is a dissociative anesthetic agent which blocks the excitatory effect of N-methyl-D-aspartate (NMDA) in the central nervous system. To investigate the role of the PCP reactive site in the control of NMDA activation of hippocampal pyramidal cells, we have examined the action of PCP and some of its analogues on the response properties of single NMDA receptors. Application of NMDA (5-15 microM) to outside-out patches of membrane elicited bursts of ion channel openings which were greatly reduced in frequency and duration in the presence of PCP (2.5-10 microM) or m-amino-PCP (2.5-10 microM), a behaviorally active derivative of PCP. These effects of PCP were reversed when the membrane potential was shifted from negative to positive values. Application of the behaviorally inactive agent 1-piperidino-cyclohexanecarbonitrile (greater than or equal to 220 microM) left NMDA-activated currents relatively unaltered. Treatment with another analogue, m-nitro-PCP (5-20 microM), resulted in an unexpected increase in frequency of openings. At a higher concentration (100-300 microM), however, m-nitro-PCP acted like PCP in reducing frequency of opening and channel life-time. Like PCP, these effects of m-nitro-PCP were reversed at positive potentials. Taken together, these results suggest that PCP and its derivatives block the open state of the NMDA channel. Moreover, the dual effect of m-nitro-PCP shows that excitability is not necessarily decreased by PCP analogues but may instead be enhanced depending on modifications of the PCP molecule.
苯环己哌啶（PCP）是一种分离麻醉剂，可阻断中枢神经系统中N-甲基-D-天冬氨酸（NMDA）的兴奋作用。为了研究PCP反应位点在控制海马锥体细胞NMDA激活中的作用，我们研究了PCP及其一些类似物对单个NMDA受体反应特性的影响。将NMDA（5 - 15微摩尔）应用于膜的外翻片会引发离子通道开放的爆发，在存在PCP（2.5 - 10微摩尔）或间氨基PCP（2.5 - 10微摩尔，PCP的一种具有行为活性的衍生物）时，其频率和持续时间会大大降低。当膜电位从负值变为正值时，PCP的这些作用会逆转。应用无行为活性的药物1 - 哌啶基 - 环己烷甲腈（大于或等于220微摩尔）时，NMDA激活的电流相对未改变。用另一种类似物间硝基PCP（5 - 20微摩尔）处理会导致开放频率意外增加。然而，在较高浓度（100 - 300微摩尔）时，间硝基PCP的作用类似于PCP，会降低开放频率和通道寿命。与PCP一样，间硝基PCP的这些作用在正电位时会逆转。综上所述，这些结果表明PCP及其衍生物会阻断NMDA通道的开放状态。此外，间硝基PCP的双重作用表明，PCP类似物不一定会降低兴奋性，而是可能根据PCP分子的修饰而增强兴奋性。
