Pharmacophoric Requirements for Cannabinoid Side Chains:  Multiple Bond and C1‘-Substituted Δ⁸-Tetrahydrocannabinols

Abstract

Accumulated evidence indicates that within the cannabinoid structure the aliphatic side chain plays a pivotal role in determining cannabimimetic activity. We describe the synthesis and affinities for the CB1 and CB2 receptors of a series of novel delta 8-THC analogues in which the side-chain pharmacophores are conformationally more defined than in the parent molecule. No analogue has the side-chain pharmacophore in a fully restricted conformation. However, our design serves to narrow down the scope of options for conformational requirements at the receptor active sites. All the analogues tested showed nanomolar or subnanomolar affinities for the receptors; 2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H- dibenzo[b,d]pyranyl)-2-hexyl-1,3-dithiolane was found to possess very high affinity for both cannabinoid receptors (CB1, Ki = 0.32 nM; CB2, Ki = 0.52 nM).

(-)-7′-Isothiocyanato-11-hydroxy-1′,1′-dimethylheptylhexahydrocannabinol (AM841), a High-Affinity Electrophilic Ligand, Interacts Covalently with a Cysteine in Helix Six and Activates the CB1 Cannabinoid Receptor

“…Our results also argue that the interaction of the cannabinoid C-3 alkyl side chain with the CB1 receptor is of a preferably hydrophobic nature and is governed by strict size considerations with respect to the ligandreceptor interacting groups. In their totality, the binding data with the cannabinergic ligands used in this study provide validation for the generally accepted cannabinoid SAR according to which major changes in ligand affinity, efficacy, and potency are modulated by manipulations of the key C-3 side chain pharmacophore (Papahatjis et al, 1998;Martin et al, 1999;Luk et al, 2004).…”

The role of halogen substitution in classical cannabinoids: A CB1 pharmacophore model

“…This observation is congruent with the presence of a hydrophobic subsite at CB1 as has been discussed in our earlier publications. 26,36,37 However, the situation is very different in the 1'-iodo-analog (36), where the presence of one iodo group results in a severe reduction in affinity for the CB1 receptor. This finding reflects either the inability of the CB1 subsite to accommodate a large group such as an iodo substituent or the effect that the halogen may have on the preferred conformation of the side chain.…”

“…We have recently described 26 the efficient synthesis of an equally populated diastereomeric mixture of (-)-1'-hydroxyheptyl-∆ 8 -tetrahydrocannabinol 35. This compound has served as the starting material for the synthesis of corresponding (-)-1'-iodo-heptyl-∆ 8 -tetrahydrocannabinol 36, using the triphenylphosphine, iodine, imidazole method (Scheme 7).…”

Synthesis of Novel Cannabinoid Ligands and Their Use as Anti-Glioma and Anti-Inflammatory Agents

“…Our binding affinity data show that compounds with a hydroxyl 8 and carbonyl linker (compounds 9 and 10) retain affinity for the CB2 receptor when compared to the gem dimethyl analog 11. The presence of the gem dimethyl group as a linker in compound 11 130 indicate that these C10 substituents reduce cannabinoid receptor affinity. Interestingly, binding affinity data for these first four compounds show that the carbonyl and hydroxyl substituents at the C10 position selectively decrease CB1 receptor affinity without altering CB2 receptor binding.…”

“…Many studies have been performed in an attempt to elucidate the SAR of the classical cannabinoids with respect to modifications of the tricyclic ring and side chain substituents at the C-3 position. Some of the different side chain modifications that have been reported thus far include the branched chain alkyls, 153 unsaturated alkyls, 130,154 and alkyls that contain a 1',1'-cyclic functionality. 155 Each of these modifications has been directed at the goal of producing compounds that have higher binding affinities for the cannabinoid receptors and also that are selective for one subtype over the other.…”