| Interaction of the NMDA receptor noncompetitive antagonist MK-801 with model and native membranes. | |
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MedLine Citation:
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PMID: 7696477 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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J Moring; L A Niego; L M Ganley; M W Trumbore; L G Herbette |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Biophysical journal Volume: 67 ISSN: 0006-3495 ISO Abbreviation: Biophys. J. Publication Date: 1994 Dec |
Date Detail:
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Created Date: 1995-05-03 Completed Date: 1995-05-03 Revised Date: 2010-09-10 |
Medline Journal Info:
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Nlm Unique ID: 0370626 Medline TA: Biophys J Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 2376-86 Citation Subset: IM |
Affiliation:
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Department of Psychiatry, University of Connecticut Health Center, Farmington 06030. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biophysical Phenomena Biophysics Calorimetry, Differential Scanning Cerebral Cortex / chemistry Cholesterol / chemistry Dizocilpine Maleate / chemistry, pharmacokinetics, pharmacology* Kinetics Lipid Bilayers / chemistry, metabolism Liposomes / chemistry Membrane Lipids / chemistry*, metabolism Membranes, Artificial* Phosphatidylcholines / chemistry Rats Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors* Synaptosomes / chemistry, drug effects, metabolism Water / chemistry X-Ray Diffraction |
| Grant Support | |
ID/Acronym/Agency:
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5 K 21 AA00126/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Lipid Bilayers; 0/Liposomes; 0/Membrane Lipids; 0/Membranes, Artificial; 0/Phosphatidylcholines; 0/Receptors, N-Methyl-D-Aspartate; 10015-85-7/1,2-oleoylphosphatidylcholine; 57-88-5/Cholesterol; 77086-22-7/Dizocilpine Maleate; 7732-18-5/Water |
| Comments/Corrections | |
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