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Molecular Pharmacology, Vol 12, 263-278, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Nuclear Magnetic Resonance Studies of Barbiturate-Phospholipid Interactions

R. F. NOVAK 1 and T. J. SWIFT 1

1 Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106

Interactions between phenobarbital or pentobarbital with the phospholipids phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, and cardiolipin were indicated by the effects of added phospholipid on the 1H magnetic resonance spectra of these barbiturates. Similar studies with phosphatidylserine gave no indication of interaction between phospholipid and the barbiturates at a comparable phospholipid concentration. Of the two barbiturates studies, phenobarbital produced the greater spectral change at a given phospholipid to barbiturate ratio. The interactions of the barbiturates with the phospholipids were further characterized using 31P and 13C magnetic resonance. Addition of barbiturate to phospholipid produced marked upfield shifts in the respective 31P peaks of the phospholipids. 13C studies verified that protonation of the basic phosphate group of the phospholipids by the weakly acidic N-H proton of the barbiturate did not account for the observed spectral changes. The direction, magnitude, and temperature dependence of the observed changes in chemical shifts in the proton and phosphorus magnetic resonance spectra are consistent with hydrogen bonding as the mode of association of the barbiturates with the phospholipids. These studies specifically identified the molecular sites of interaction as an N-H moiety of the barbiturate and the phosphate group of the phospholipid, and allowed determination of the association constants for the interactions in chloroform: Kassoc for the various barbiturate-phospholipid pairs ranged from 175 to 25, the latter value corresponding to the phosphatidylethanolamine-phenobarbital interaction. The results are discussed in terms of a model for the interaction of barbiturates with membranes.

Note:
ACKNOWLEDGMENTS We thank Drs. John J. Mieyal and Cecil Cooper for their stimulating discussions and many useful suggestions.

Submitted on April 22, 1975






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