Interaction of the NMDA receptor noncompetitive antagonist MK-801 with model and native membranes.
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.
Moring
J
J
Department of Psychiatry, University of Connecticut Health Center, Farmington 06030.
Niego
L A
LA
Ganley
L M
LM
Trumbore
M W
MW
Herbette
L G
LG
D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D002152:Calorimetry, Differential Scanning; D002540:Cerebral Cortex / Q000737:chemistry; D002784:Cholesterol / Q000737:chemistry; D016291:Dizocilpine Maleate / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism; D008567:Membranes, Artificial; D010713:Phosphatidylcholines / Q000737:chemistry; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
D008051:Lipid Bilayers; D008081:Liposomes; D008563:Membrane Lipids; D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D016194:Receptors, N-Methyl-D-Aspartate; D014867:Water; D016291:Dizocilpine Maleate; D002784:Cholesterol; C017251:1,2-oleoylphosphatidylcholine