QSAR Analysis of Δ⁸-THC Analogues:  Relationship of Side-Chain Conformation to Cannabinoid Receptor Affinity and Pharmacological Potency

Abstract

A novel quantitative structure-activity relationship (QSAR) for the side-chain region of Delta(8)-tetrahydrocannabinol (Delta(8)-THC) analogues is reported. A series of 36 side-chain-substituted Delta(8)-THCs with a wide range of pharmacological potency and CB1 receptor affinity was investigated using computational molecular modeling and QSAR analyses. The conformational mobility of each compound's side chain was characterized using a quenched molecular dynamics approach. The QSAR techniques included a modified active analogue approach (MAA), multiple linear regression analyses (MLR), and comparative molecular field analysis (CoMFA) studies. All three approaches yielded consistent results. The MAA approach applied to a set of alkene/alkyne pairs identified the most active conformers as those with conformational mobility constrained within an approximately 8 A radius. MLR analyses (restricted to 15 hydrocarbon side-chain analogues) identified two variables describing side-chain length and terminus position that were able to fit the pharmacological data for receptor affinity with a correlation coefficient 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. Therefore, the side chain's conformational mobility must not restrict the chain straight away from the ring system but must allow the chain to wrap back around toward the ring system. Finally, the CoMFA analyses involved all 36 analogues; they also provided data to support the hypothesis that for optimum affinity and potency the side chain must have conformational freedom that allows its terminus to fold back and come into proximity with the phenolic ring.

3D-QSAR Studies on Cannabinoid CB1 Receptor Agonists: G-Protein Activation as Biological Data

“…Comparative molecular field analysis 19 (CoMFA), a threedimensional quantitative structure-activity relationship (3D-QSAR) method that utilizes ligand SAR, has been employed to obtain indirect information about the CB1 binding site. The reported CoMFA models are based either on SAR from one structural class of ligands [20][21][22][23][24][25][26] or from two or more classes of ligands. [27][28][29][30] For the latter models, research groups have attempted to derive common pharmacophoric alignments of structurally different cannabinergic ligands, based on the fact that the ligands displace one another in radioligand binding assays.…”

Characterization of rat liver microsomal metabolites of AM‐630, a potent cannabinoid receptor antagonist, by high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry

“…The discovery of the central and peripheral cannabinoid receptors (CB 1 and CB 2 ) has prompted the development of many receptor‐binding compounds for use in cannabinoid research and for potential therapeutic applications 1. These include tricyclic and bicyclic cannabinoids that are structurally similar to cannabinoids found in marijuana,2, 3 aminoalkylindoles (AAIs), which are derived from pravadoline with potent antinociceptive activity,4–7 endogenous ligands such as anandamides and 2‐arachidonoylglycerol8, 9 and diarylpyrazole analogues that behave as antagonists/inverse agonists for CB 1 and CB 2 10–12…”

In Vitro Metabolism of Diarylpyrazoles, a Novel Group of Cannabinoid Receptor Ligands

“…The role of CB 2 in mediating physiological effects has not been fully determined, but it is believed that CB 2 may be involved in cannabinoid-mediated immune responses (Bouaboula et al, 1999;Portier et al, 1999). A large variety of compounds have been found to bind to the receptors, including natural and synthetic cannabinoids (Razdan, 1986;Keimowitz et al, 2000), aminoalkylindoles (Bell et al, 1991;Shim et al, 1998), endogenous ligands, and diarylpyrazoles (Compton et al, 1993;Wiley et al, 2001).…”