QSAR analysis of Delta(8)-THC analogues: Relationship of side-chain conformation to cannabinoid receptor affinity and pharmacological potency

A novel quantitative structure-activity relationship (QSAR) for the side-ch ain region of Delta(8)- tetrahydrocannabinol (Delta(8)-THC) analogues is re ported. A series of 36 side-chain-substituted Delta(8)-THCs with a wide ran ge of pharmacological potency and CB1 receptor affinity was investigated us ing computational molecular modeling and QSAR analyses. The conformational mobility of each compound's side chain was characterized using a quenched m olecular dynamics approach. The QSAR techniques included a modified active analogue approach (MAA), multiple linear regression analyses (MLR), and com parative molecular field analysis (CoMFA) studies. All three approaches yie lded consistent results. The MAA approach applied to a set of alkene/alkyne pairs identified the most active conformers as those with conformational m obility constrained within an approximately 8 Angstrom radius. MLR analyses (restricted to 15 hydrocarbon side-chain analogues) identified two variabl es describing side-chain length and terminus position that were able to fit the pharmacological data for receptor affinity with a correlation coeffici ent for pK(D) of 0.82. While chain length was found to be directly related to receptor affinity, the angle made by the side chain from its attachment point to its terminus (angle defined by C3- C1'-side-chain terminus carbon, see Figure 1) was found to be inversely related to affinity. These results suggest that increased side-chain length and increased side-chain ability to wrap around the ring system are predicted to increase affinity. Therefor e, the side chain's conformational mobility must not restrict the chain str aight away from the ring system but must allow the chain to wrap back aroun d toward the ring system. Finally, the CoMFA analyses involved all 36 analo gues; they also provided data to support the hypothesis that for optimum af finity and potency the side chain must have conformational freedom that all ows its terminus to fold back and come into proximity with the phenolic rin g.