The conformation of (-) 8 alpha and (-) 8 beta-hydroxy-delta 9-tetrahydrocannabinols and their interactions with model membranes.
8 alpha- and 8 beta-Hydroxy-delta 9-tetrahydrocannabinols (THC's), two metabolites of the naturally occurring delta 9-THC have been shown to possess differences in pharmacological activity. We have studied the conformations of these two compounds, as well as their interactions with model membrane systems and compared them with delta 9-THC. The conformational study, carried out in solution and using high resolution NMR indicated that differences in the ring conformations of these two compounds were negligible but that the 8-hydroxy group of the 8 beta-OH compound extended approximately 1.4A higher above the plane of the aromatic ring than in the 8 alpha-OH isomer. This difference could prove significant in the interaction of these molecules with lipid bilayers. We found that both 8 alpha- and 8 beta-OH analogs affected the melting behavior of hydrated DPPC bilayers including a lowering of the main transition temperature (Tc), a broadening of that transition and the abolishment of the pretransition of DPPC. The effects of the more active compound, 8 beta-OH-delta 9-THC on the model membrane approximated closely those of delta 9-THC, while the less active 8 alpha-OH epimer produced different thermotropic changes.
Van der Schyf
C J
CJ
Department of Medicinal Chemistry and Pharmacognosy, University of Connecticut, Storrs 06268.
Mavromoustakos
T
T
Makriyannis
A
A
D015060:1,2-Dipalmitoylphosphatidylcholine; D002152:Calorimetry, Differential Scanning; D002784:Cholesterol / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008051:Lipid Bilayers; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D013816:Thermodynamics
D008051:Lipid Bilayers; D015060:1,2-Dipalmitoylphosphatidylcholine; C033935:8-hydroxy-delta(9)-tetrahydrocannabinol; D013759:Dronabinol; D002784:Cholesterol