Solid state 2H-NMR as a method for determining the orientation of cannabinoid analogs in membranes.
In order to investigate the correlation between the pharmacological activities of cannabinoids and the geometric features of their interactions with membranes, we have calculated the molecular orientations of five analogs in model membrane bilayers. The studies involved the stereospecific 2H-labeling of each analog in different positions and the use of solid state 2H-NMR. The cannabinoids included in our study are (-)-delta 9-tetrahydrocannabinol (THC), (-)-delta 8-THC and its methylated ether analog (-)-O-methyl-delta 8-THC, as well as two hexahydrocannabinols (HHC) having an additional hydroxyl in the 11-position, (-)-11-OH-9 alpha-HHC and (-)-11-OH-9 beta-HHC. A new algorithm is used to circumvent the problem of deuterium quadrupolar splitting signs. The method has general applicability for calculating the orientation of a molecule in a anisotropic environment. Our calculations show that the biological inactive O-methyl-delta 8-THC orients with its long axis parallel to the lipid acyl chains, whereas the psychoactive cannabinoids assume "awkward" orientations in which the hydroxyl groups are pointing towards the bilayer interface, presumably to maximize the amphipathic interaction with the membrane. To produce their biological effects, cannabinoids may need to acquire an appropriate location and orientation in the membrane bilayer so that, through lateral diffusion, they can reach their sites of action and interact productively with these sites.
Yang
D P
DP
Section of Medicinal Chemistry and Pharmacognosy, School of Pharmacy, University of Connecticut, Storrs 06269.
Banijamali
A
A
Charalambous
A
A
Marciniak
G
G
Makriyannis
A
A
D002186:Cannabinoids / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D009682:Magnetic Resonance Spectroscopy; D008566:Membranes / Q000737:chemistry; D008968:Molecular Conformation
D002186:Cannabinoids