In earlier work we have provided evidence for the presence of a subsite within the CB1 and CB2 cannabinoid receptor binding domains of classical cannabinoids. This putative subsite corresponds to substituents on the C1'-position of the C3-alkyl side chain, a key pharmacophoric feature in this class of compounds. We have now refined this work through the synthesis of additional C1'-cycloalkyl compounds using newly developed approaches. Our findings indicate that the C1'-cyclopropyl and C1'-cyclopentyl groups are optimal pharmacophores for both receptors while the C1'-cyclobutyl group interacts optimally with CB1 but not with CB2. The C1'-cyclohexyl analogs have reduced affinities for both CB1 and CB2. However, these affinities are significantly improved with the introduction of a C2'-C3' cis double bond that modifies the available conformational space within the side chain and allows for a better accommodation of a six-membered ring within the side chain subsite. Our SAR results are highlighted by molecular modeling of key analogs.

Terpenes Terpenes U 0200Novel 1',1'-Chain Substituted ∆ 8 -Tetrahydrocannabinols. -The 1',1'-gem-dimethyl group in the side chain of (-)-∆ 8 -tetrahydrocannabinol is substituted with a sterical more confined cyclopropyl group and additionally, a gem-dihalo substitution at the C-2'' of the cyclopropyl ring is carried out to probe the stereochemical limits of the new pharmacophore. The procedure for the synthesis of analogues (VIII) and (XV) involves terpenylation of resorcinol derivatives (V) and (XIV) with menthadienol (VI) followed by a clean cyclization reaction. The novel side chain substituents enhance the affinities of ∆ 8 -tetrahydrocannabinol and cannabidiol analogues for the CB1 and CB2 cannabinoid receptors. -(PAPAHATJIS*, D. P.; NIKAS, S. P.; ANDREOU, T.; MAKRIYANNIS, A.; Bioorg. Med.

A set of 30 novel Delta8-tetrahydrocannabinol and cannabidiol analogues were subjected to three-dimensional quantitative structure-activity relationship studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. Using a combination of molecular modeling techniques and NMR spectroscopy, the putative bioactive conformation of the most potent cannabinoid (CB) ligand in the training set was determined. This conformer was used as the template and CB1 and CB2 pharmacophore models were developed. These models were fitted with experimental binding data and gave high correlation coefficients. Contour maps of the CB1 and CB2 models of CoMFA and CoMSIA approaches show that steric effects dominantly determine the binding affinities. The CoMFA and CoMSIA analyses based on the binding affinity data of CB ligands at the CB1 and CB2 receptors allowed us to deduce the possible optimal binding positions. This information can be used for the design of new CB analogues with enhanced activity and other tailored properties.