Gandolfi O, Bonfante V, Voltattorni M, Dall'Olio R, Poli A, Pietra C, Villetti G
Department of Pharmacology, University of Bologna, via Irnerio 48, 40126, Bologna, Italy.
Pharmacol Biochem Behav. 2001 Sep;70(1):157-66. doi: 10.1016/s0091-3057(01)00591-3.
Following intraperitoneal or oral administrations, CHF 3381 ([n-(2-indanyl)-glycinamide hydrochloride]) protected rats against maximal electroshock (MES) test seizures. As glutamatergic pathways play a pivotal role in epilepsy, to better characterize the molecular mechanisms of action of CHF 3381, the drug effects on the binding of the excitatory amino acid antagonist [3H]-MK-801 in the presence of n-methyl-D-aspartate (NMDA), spermidine, or the combination of both ligands, were studied. CHF 3381 inhibited the [3H]-MK-801 specific binding in a noncompetitive fashion in respect to NMDA and polyamines recognition sites. CHF 3381 failed to change the kinetic characteristic of glycine B receptors labeled with [3H]-glycine; in contrast, it significantly increased K(d) values when the receptors were labeled with the more specific compound [3H]-MDL 105,519. CHF 3381 antagonized dopamine (DA)-induced behavioral responses and inhibited, in a glycine-dependent manner, the NMDA-induced [3H]-DA release from rat striatal slices, but it failed to change either the kinetic characteristics of D1, D2, or D3 receptors in synaptic plasma membranes (SPM) or the [3H]-DA uptake from striatal synaptosomes. Moreover, in primary cell cultures of cortical neurons, this drug exhibited glycine-independent neuroprotective effects against glutamate-induced excitotoxicity. It is concluded that this compound could have a potential use in several disease states where a pathological high level of NMDA receptor activation is thought to occur.
腹腔注射或口服CHF 3381（盐酸N-(2-茚满基)-甘氨酰胺）后，可保护大鼠免受最大电休克（MES）试验性癫痫发作。由于谷氨酸能通路在癫痫中起关键作用，为了更好地表征CHF 3381的分子作用机制，研究了该药物在存在N-甲基-D-天冬氨酸（NMDA）、亚精胺或两种配体组合的情况下对兴奋性氨基酸拮抗剂[3H]-MK-801结合的影响。CHF 3381以非竞争性方式抑制相对于NMDA和多胺识别位点的[3H]-MK-801特异性结合。CHF 3381未能改变用[3H]-甘氨酸标记的甘氨酸B受体的动力学特征；相反，当用更特异性的化合物[3H]-MDL 105,519标记受体时，它显著增加了K(d)值。CHF 3381拮抗多巴胺（DA）诱导的行为反应，并以甘氨酸依赖性方式抑制NMDA诱导的大鼠纹状体切片中[3H]-DA的释放，但它未能改变突触质膜（SPM）中D1、D2或D3受体的动力学特征，也未能改变纹状体突触体对[3H]-DA的摄取。此外，在皮质神经元的原代细胞培养中，该药物对谷氨酸诱导的兴奋性毒性表现出不依赖甘氨酸的神经保护作用。结论是，该化合物可能在几种被认为发生NMDA受体病理性高水平激活的疾病状态中有潜在用途。
