C1‘-Cycloalkyl Side Chain Pharmacophore in Tetrahydrocannabinols

Abstract

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.

AM2389, a high-affinity, in vivo potent CB1-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice

“…Earlier work aimed at defining the pharmacophoric elements of the cannabinoid side chain led to novel Δ 8 -THC analogs that bear cyclic moieties at the C1' position of the side chain (Papahatjis et al 1998, 2002, 2003, 2007). Aforementioned studies resulted in Δ 8 -THC analogs with high affinities for the two cloned cannabinoid receptors, CB 1 R and CB 2 R, and provided a starting point for developing more subtype-selective second-generation ligands.…”

Design and Synthesis of (13S)‐Methyl‐Substituted Arachidonic Acid Analogues: Templates for Novel Endocannabinoids

“…[4, 44, 45, 47, 64, 65] For the CB1 receptor, binding data were obtained by using a rat brain membrane in the presence of phenylmethanesulfonyl fluoride (PMSF), [66, 67] a general serine protease inhibitor that is used to protect the analogues from the hydrolytic activity of fatty acid amide hydrolase (FAAH). [43, 67] Rat brain membranes have a high concentration of CB1 receptors without significant CB2 receptors present.…”

“…For CB1, rat forebrain membranes were prepared according to the procedure of Dodd et al[69] The binding of the novel anandamide analogues to the cannabinoid receptor was assessed as previously described,[4, 44, 45, 47, 64, 65] except that the membranes were pre-treated with PMSF. Membranes, previously frozen at −80°C, were thawed on ice.…”

Synthesis, radio-synthesis and in vitro evaluation of terminally fluorinated derivatives of HU-210 and HU-211 as novel candidate PET tracers

“…The synthesis of 1 started with the methylation 8 of commercially available (3,5-dimethoxyphenyl)acetonitrile (3), that afforded the α,α-dimethylnitrile 4 in excellent yield. Subsequent hydride reduction 9 of 4 afforded the aldehyde 5, which was subjected to a Wittig olefination 9 with the ylide generated 10 from the phosphonium salt 6 that yielded the unsaturated alcohol 7 as a single isomer, presumably having (Z)-geometry. The C=C bond of 7 was then hydrogenated (Pd/C, H 2 , in EtOAc) 9 to give compound 8 in quantitative yield.…”

“…Subsequent hydride reduction 9 of 4 afforded the aldehyde 5, which was subjected to a Wittig olefination 9 with the ylide generated 10 from the phosphonium salt 6 that yielded the unsaturated alcohol 7 as a single isomer, presumably having (Z)-geometry. The C=C bond of 7 was then hydrogenated (Pd/C, H 2 , in EtOAc) 9 to give compound 8 in quantitative yield. During a first Odemethylation attempt (BBr 3 in DCM from -78°C to -10 °C) 11 an undesired replacement of the primary OH of 8 with a Br atom occurred, leading to the corresponding alkyl bromide.…”