3′-Functionalized Adamantyl Cannabinoid Receptor Probes

Abstract

The aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids, and we have previously shown that this chain could be substituted successfully by adamantyl or other polycyclic groups. In an effort to explore the pharmacophoric features of these conformationally fixed groups, we have synthesized a series of analogues in which the C3 position is substituted directly with an adamantyl group bearing functionality at one of the tertiary carbon atoms. These substituents included the electrophilic isothiocyanate and photoactivatable azido groups, both of which are capable of covalent attachment with the target protein. Our results show that substitution at the 3′-adamantyl position can lead to ligands with improved affinities and CB1/CB2 selectivities. Our work has also led to the development of two successful covalent probes with high affinities for both cannabinoid receptors, namely, the electrophilic isothiocyanate AM994 and the photoactivatable aliphatic azido AM993 analogues.

Crystal Structure of the Human Cannabinoid Receptor CB2

“…The above analysis indicated a critical role of the toggle switch residue Trp258 6.48 during CB2 activation and an essential function of arm 1 of the ligand for CB2 antagonism. Interestingly, our functional data showed that MRI2687 also acts as a partial agonist on CB1 ( Figure 6D), further supporting the notion that CB2 antagonist and CB1 agonist profiles probably occur in certain compounds (Ogawa et al, 2015), representing a CB2 and CB1 yin-yang functional relationship. The physiological im-plications of such opposing activation profiles between CB1 and CB2 are worth exploring further.…”

Synthesis of Functionalized Cannabilactones

“…Cannabilactone analogs with modifications at the C3 side chain were prepared following the general method used for the synthesis of AM1710 (Scheme 3b-f). The design of these analogs was influenced by our earlier SAR work on the C3 side chain of tricyclic tetrahydrocannabinols (THCs) and hexahydrocannabinols (HHCs) [21,23,24,[28][29][30][31][32]. The addition of the larger cyclopentyl ring at C1 was attempted to explore the effect of the size of the benzylic substituents.…”

Novel C-Ring-Hydroxy-Substituted Controlled Deactivation Cannabinergic Analogues

“…19,20 Our testing results (Table 2) show that all three compounds potently decreased the levels of cAMP, indicating that within this signaling mechanism these compounds behaved as potent agonists at both the CB1 and CB2 receptors with the 11-OH-HHC ester analogue 3b being the most potent.…”

“…We and others have observed that this condensation works well with resorcinols bearing electron donating alkyl side chains with bulky groups at the benzylic position including the 5-(1,1-dimethylheptyl)resorcinol. 18–20,26 This, coupled with our earlier investigations on the mechanism of this condensation, 25 led us to postulate that presence of the carboxyester group in 13 decreases the electron density of the aromatic ring and slows down the rate of the initial Friedel–Crafts allylation reaction. Thus, the acid catalyzed decomposition of diacetates 14 to give 14a and the monoacetylation of 13 to give 13a become important side reactions.…”

“…13,20 EC 50 values were calculated using nonlinear regression analysis. Data are the average of two independent experiments run in triplicate, and 95% confidence intervals for the EC 50 values are given in parentheses.…”