Yang D P, Banijamali A, Charalambous A, Marciniak G, Makriyannis A
Section of Medicinal Chemistry and Pharmacognosy, School of Pharmacy, University of Connecticut, Storrs 06269.
Pharmacol Biochem Behav. 1991 Nov;40(3):553-7. doi: 10.1016/0091-3057(91)90362-6.
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.
为了研究大麻素的药理活性与其与膜相互作用的几何特征之间的相关性，我们计算了五种类似物在模型膜双层中的分子取向。这些研究涉及对每个类似物在不同位置进行立体特异性的2H标记，并使用固态2H-NMR。我们研究中所包含的大麻素包括(-)-δ9-四氢大麻酚(THC)、(-)-δ8-THC及其甲基化醚类似物(-)-O-甲基-δ8-THC，以及两种在11位有额外羟基的六氢大麻酚(HHC)，即(-)-11-OH-9α-HHC和(-)-11-OH-9β-HHC。我们使用了一种新算法来规避氘四极分裂符号的问题。该方法对于计算分子在各向异性环境中的取向具有普遍适用性。我们的计算表明，无生物活性的O-甲基-δ8-THC的长轴与脂质酰基链平行，而具有精神活性的大麻素呈现“别扭”的取向，其中羟基指向双层界面，大概是为了最大化与膜的两亲性相互作用。为了产生其生物学效应，大麻素可能需要在膜双层中获得合适的位置和取向，以便通过横向扩散，它们能够到达其作用位点并与这些位点进行有效的相互作用。
