Arai Amy C, Xia Yan-Fang, Rogers Gary, Lynch Gary, Kessler Markus
Department of Pharmacology, Southern Illinois University, Springfield, Illinois 62702, USA.
J Pharmacol Exp Ther. 2002 Dec;303(3):1075-85. doi: 10.1124/jpet.102.040360.
CX516 (BDP-12) and CX546, two first-generation benzamide-type AMPA receptor modulators, were compared with regard to their influence on AMPA receptor-mediated currents, autaptic responses in cultured hippocampal neurons, hippocampal excitatory postsynaptic currents, synaptic field potentials, and agonist binding. The two drugs exhibited comparable potencies in most tests but differed in their efficacy and in their relative impact on various response parameters. CX546 greatly prolonged the duration of synaptic responses, and it slowed 10-fold the deactivation of excised-patch currents following 1-ms pulses of glutamate. The effects of CX516 on those measures were, by comparison, small; however, the drug was equally or more efficacious than CX546 in increasing the amplitude of synaptic responses. This double dissociation suggests that amplitude and duration of synaptic responses are governed by different aspects of receptor kinetics, which are differentially modified by the two drugs. These effects can be reproduced in receptor simulations if one assumes that CX516 preferentially accelerates channel opening while CX546 slows channel closing. In binding tests, CX546 caused an approximately 2-fold increase in the affinity for radiolabeled agonists, whereas CX516 was ineffective. More importantly, even millimolar concentrations of CX516 did not influence the dose-response relation for CX546, suggesting the possibility that they bind to different sites. Taken together, the evidence suggests that benzamide modulators from the Ampakine family form two subgroups with different modes and sites of action. Of these, CX516-type drugs may have the greater therapeutic utility because of their limited efficacy in prolonging synaptic responses and in attenuating receptor desensitization.
将第一代苯甲酰胺型AMPA受体调节剂CX516（BDP - 12）和CX546，在对AMPA受体介导的电流、培养海马神经元中的自突触反应、海马兴奋性突触后电流、突触场电位及激动剂结合的影响方面进行了比较。在大多数测试中，这两种药物表现出相当的效力，但在疗效以及对各种反应参数的相对影响方面存在差异。CX546极大地延长了突触反应的持续时间，并且使在1毫秒谷氨酸脉冲后切除膜片电流的失活速度减慢了10倍。相比之下，CX516对这些指标的影响较小；然而，在增加突触反应幅度方面，该药物与CX546同样有效或更有效。这种双重解离表明，突触反应的幅度和持续时间受受体动力学不同方面的支配，而这两种药物对其有不同的修饰作用。如果假设CX516优先加速通道开放而CX546减慢通道关闭，那么这些效应可以在受体模拟中重现。在结合试验中，CX546使对放射性标记激动剂的亲和力增加了约2倍，而CX516则无效。更重要的是，即使是毫摩尔浓度的CX516也不影响CX546的剂量反应关系，这表明它们可能结合到不同位点。综上所述，证据表明来自安帕金家族的苯甲酰胺调节剂形成了两个具有不同作用模式和位点的亚组。其中，CX516型药物可能具有更大的治疗效用，因为它们在延长突触反应和减弱受体脱敏方面的效力有限。
