Parsons C G, Hartmann S, Spielmanns P
Department of Pharmacology, Merz and Co., Frankfurt, Germany.
Neuropharmacology. 1998 Jun;37(6):719-27. doi: 10.1016/s0028-3908(98)00059-8.
The NMDA receptor antagonistic effects of budipine were assessed using concentration- and patch-clamp techniques on cultured striatal, hippocampal, cortical and superior colliculus neurones. Inward current responses of striatal neurones to NMDA (200 microM) at -70 mV were antagonized by budipine in a concentration-dependent manner (50% inhibitory concentration (IC50) 59.4 +/- 10.7 microM, n = 17) with 24 times lower potency than memantine but similar potency to amantadine. In striatal neurones, budipine blocked outward currents at +70 mV with an IC50 of 827 microM, suggesting that the binding site is less deep in the channel (delta = 0.45) than for memantine. However, more detailed analysis of the fractional block by budipine 300 microM in hippocampal neurones gave a delta-value of 0.90, but revealed that 28% block is mediated at a voltage-independent site. This voltage-insensitive site was accessible in the absence of agonist. Budipine exhibited concentration-dependent open channel blocking kinetics (kappa(on) = 0.71 x 10(4) M(-1) s(-1)) whereas the fast offset rate was concentration-independent (kappa(off) = 0.63 s(-1)). Calculation of the ratio kappa(off)/kappa(on) revealed an apparent Kd value of 88.7 microM. Budipine, memantine and amantadine had similar effects against NMDA-induced currents in cultured hippocampal, cortical and superior colliculus neurones, although amantadine was somewhat more potent in cultured striatal neurones. The relevance of NMDA receptor antagonism to the anti-Parkinsonian effects of budipine remains to be established.
使用浓度和膜片钳技术，在培养的纹状体、海马体、皮质和上丘神经元上评估了布地品的N-甲基-D-天冬氨酸（NMDA）受体拮抗作用。在-70 mV时，布地品以浓度依赖性方式拮抗纹状体神经元对NMDA（200 μM）的内向电流反应（50%抑制浓度（IC50）为59.4±10.7 μM，n = 17），其效力比美金刚低24倍，但与金刚烷胺效力相似。在纹状体神经元中，布地品在+70 mV时阻断外向电流，IC50为827 μM，这表明其结合位点在通道中的深度（δ = 0.45）比美金刚浅。然而，对海马神经元中300 μM布地品的分数阻断进行更详细分析得出δ值为0.90，但显示28%的阻断是在电压非依赖性位点介导的。在没有激动剂的情况下，这个电压不敏感位点是可及的。布地品表现出浓度依赖性的开放通道阻断动力学（κ(on) = 0.71×10⁴ M⁻¹ s⁻¹），而快速解离速率与浓度无关（κ(off) = 0.63 s⁻¹）。κ(off)/κ(on)比值的计算得出表观解离常数（Kd）值为88.7 μM。布地品、美金刚和金刚烷胺对培养的海马体、皮质和上丘神经元中NMDA诱导的电流具有相似的作用，尽管金刚烷胺在培养的纹状体神经元中效力稍强。NMDA受体拮抗作用与布地品抗帕金森病作用的相关性仍有待确定。
