Moring J, Niego L A, Ganley L M, Trumbore M W, Herbette L G
Department of Psychiatry, University of Connecticut Health Center, Farmington 06030.
Biophys J. 1994 Dec;67(6):2376-86. doi: 10.1016/S0006-3495(94)80724-6.
MK-801, a noncompetitive antagonist of the NMDA (N-methyl-D-aspartate) receptor, has protective effects against excitotoxicity and ethanol withdrawal seizures. We have determined membrane/buffer partition coefficients (Kp[mem]) of MK-801 and its rates of association with and dissociation from membranes. Kp[mem] (+/- SD) = 1137 (+/- 320) in DOPC membranes and 485 (+/- 99) in synaptoneurosomal (SNM) lipid membranes from rat cerebral cortex (unilamellar vesicles). In multilamellar vesicles, Kp[mem] was higher: 3374 (+/- 253) in DOPC and 6879 (+/- 947) in SNM. In cholesterol/DOPC membranes, Kp[mem] decreased as the cholesterol content increased. MK-801 associated with and dissociated from membranes rapidly. Addition of ethanol to SNM did not affect Kp[mem]. MK-801 decreased the cooperative unit size of DMPC membranes. The decrease was smaller than that caused by 1,4-dihydropyridine drugs, indicating a weaker interaction with the hydrocarbon core. Small angle x-ray diffraction, with multilayer autocorrelation difference function modeling, indicated that MK-801 in a cholesterol/DOPC membrane (mole ratio = 0.6) causes a perturbation at approximately 16.0 A from the bilayer center. In bilayers of cholesterol/DOPC = 0.15 (mole ratio) or pure DOPC, the perturbation caused by MK-801 was more complex. The physical chemical interactions of MK-801 with membranes in vitro are consistent with a fast onset and short duration of action in vivo.
MK-801是N-甲基-D-天冬氨酸（NMDA）受体的非竞争性拮抗剂，对兴奋性毒性和乙醇戒断性癫痫具有保护作用。我们已经测定了MK-801的膜/缓冲液分配系数（Kp[mem]）及其与膜的结合和解离速率。在二油酰磷脂酰胆碱（DOPC）膜中，Kp[mem]（±标准差）=1137（±320），在大鼠大脑皮质的突触神经体（SNM）脂质膜（单层囊泡）中为485（±99）。在多层囊泡中，Kp[mem]更高：在DOPC中为3374（±253），在SNM中为6879（±947）。在胆固醇/DOPC膜中，Kp[mem]随着胆固醇含量的增加而降低。MK-801与膜的结合和解离都很快。向SNM中添加乙醇不影响Kp[mem]。MK-801降低了二肉豆蔻酰磷脂酰胆碱（DMPC）膜的协同单位大小。这种降低比1,4-二氢吡啶类药物引起的要小，表明与烃核的相互作用较弱。小角X射线衍射结合多层自相关差异函数建模表明，在胆固醇/DOPC膜（摩尔比=0.6）中，MK-801在距双层中心约16.0埃处引起扰动。在胆固醇/DOPC = 0.15（摩尔比）的双层膜或纯DOPC中，MK-801引起的扰动更为复杂。MK-801在体外与膜的物理化学相互作用与体内起效快、作用持续时间短一致。
