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Conformational Study of Lipophilic Ligands in Phospholipid Model Membrane Systems by Solution NMR

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Department of Pharmaceutical Sciences, Center for Drug Discovery, The University of Connecticut, Storrs, Connecticut 06269; Department of Physics, College of the Holy Cross, Worcester, Massachusetts 01610; and The Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Cite this: J. Med. Chem. 2003, 46, 23, 4838–4846
Publication Date (Web):October 15, 2003
https://doi.org/10.1021/jm020385r
Copyright © 2003 American Chemical Society
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    Abstract

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    Phospholipid bicelles were employed as a membrane bilayer model in the conformational studies of two lipophilic cannabinoids, Δ8-THC and its O-methyl ether analogue, Me-Δ8-THC using conventional high-resolution NMR. A preparation of 8% (w/v) phospholipid concentration and a high DMPC/DHPC ratio (q = 2.0) was found to be optimal for not only effectively incorporating our ligands, but also providing a more bilayerlike environment suitable for conformational studies. While the conformational differences between the two cannabinoids could not be observed in chloroform and were barely detectable in SDS micelle solution, there is an increasing preference for the pentyl tail of Δ8-THC to bend toward the tricyclic ring system with increasing proportions of DMPC in the bicelle preparation. Our results highlight the advantages of exploring the conformational properties of cannabinoids using bicelle preparations as a medium that more closely resembles biological membrane bilayers and eliminates the need for isotopic labeling. This approach should also be of more general value for studying the interactions of other cannabinoids and biologically active, hydrophobic or amphipathic, small molecules with membranes.

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    †

     The University of Connecticut.

    ‡

     College of the Holy Cross.

    *

     Corresponding author:  Tel:  (860) 486-2133. Fax:  (860) 486-3089. E-mail:  [email protected].

    §

     Massachusetts Institute of Technology.

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