Arnt J, Sánchez C, Lenz S M, Madsen U, Krogsgaard-Larsen P
H. Lundbeck A/S, Copenhagen-Valby, Denmark.
Eur J Pharmacol. 1995 Oct 24;285(3):289-97. doi: 10.1016/0014-2999(95)00422-h.
The discriminative stimulus properties of the AMPA ((RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid) and NMDA (N-methyl-D-aspartic acid) in rats have been characterized. It is suggested that the cues are mediated by separate mechanisms in the central nervous system. The ATPA cue is not mimicked by NMDA or an NMDA receptor agonist, and is inhibited by the AMPA receptor antagonist (R)-APPA ((R)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid) but not the AMPA receptor antagonist ATOA ((RS)-2-amino-3-(3-carboxymethoxy-5-tert-butylisoxazol-4-yl)propio nic acid) or the NMDA receptor antagonist CPP ((RS)-3-(2-carboxypiperazin-4-yl)propyl)phosphonic acid). The ATPA cue is not mimicked by AMPA which is believed not to penetrate the blood-brain barrier. In contrast, ATPA does not generalize to the NMDA cue, which is mimicked by some NMDA receptor agonists (tetrazol-5-yl-glycine and AMAA ((RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid)) and is inhibited by the NMDA receptor antagonist CPP. Highly potent convulsant activity was demonstrated in mice with all AMPA and NMDA receptor agonists after intracerebroventricular (i.c.v.) injection, whereas weaker or no effects were found after subcutaneous (s.c.) or intravenous injection. Only (RS)-tetrazol-5-yl-glycine had a potent effect after s.c. administration. I.c.v. ATOA and CPP inhibited convulsions induced by i.c.v. injection of AMPA or NMDA, while (R)-APPA was ineffective. These results indicate that there are differences in the structure-activity relations in the drug discrimination and convulsant/anticonvulsant models, even when effects after i.c.v. and s.c. injection are taken into consideration. The convulsion models are rapid tests which can give an indication of central nervous system penetration, but are less pharmacologically specific with respect to differentiation between AMPA and NMDA ligands where cue models demonstrate clear differences in effects of ligands with selectivity for receptor subtypes.
已对大鼠体内α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体激动剂2-氨基-3-（3-羟基-5-叔丁基异恶唑-4-基）丙酸（ATPA）和N-甲基-D-天冬氨酸（NMDA）的辨别刺激特性进行了表征。提示在中枢神经系统中由不同机制介导。NMDA或NMDA受体激动剂无法模拟ATPA提示，且该提示可被AMPA受体拮抗剂（R）-2-氨基-3-（3-羟基-5-苯基异恶唑-4-基）丙酸（（R）-APPA）抑制，但不能被AMPA受体拮抗剂2-氨基-3-（3-羧甲氧基-5-叔丁基异恶唑-4-基）丙酸（ATOA）或NMDA受体拮抗剂3-（2-羧基哌嗪-4-基）丙基膦酸（CPP）抑制。据信无法穿透血脑屏障的AMPA无法模拟ATPA提示。相反，ATPA不会泛化至NMDA提示，某些NMDA受体激动剂（5-四氮唑基甘氨酸和2-氨基-2-（3-羟基-5-甲基异恶唑-4-基）乙酸（AMAA））可模拟该提示，且该提示可被NMDA受体拮抗剂CPP抑制。脑室内（i.c.v.）注射后，所有AMPA和NMDA受体激动剂在小鼠中均表现出高效惊厥活性，而皮下（s.c.）或静脉注射后效果较弱或无效果。仅（RS）-5-四氮唑基甘氨酸在皮下给药后有强效作用。脑室内注射ATOA和CPP可抑制脑室内注射AMPA或NMDA诱导的惊厥，而（R）-APPA无效。这些结果表明，即使考虑脑室内注射和皮下注射后的效果，药物辨别和惊厥/抗惊厥模型中的构效关系仍存在差异。惊厥模型是快速测试，可指示中枢神经系统的穿透情况，但在区分AMPA和NMDA配体方面药理学特异性较低，而提示模型显示配体对受体亚型的选择性作用存在明显差异。
