Novel Functionalized Cannabinoid Receptor Probes: Development of Exceptionally Potent Agonists

We report the development of novel cannabinergic probes that can stabilize the cannabinoid receptors (CBRs) through tight binding interactions. Ligand design involves the introduction of select groups at a judiciously chosen position within the classical hexahydrocannabinol template (monofunctionalized probes). Such groups include the electrophilic isothiocyanato, the photoactivatable azido, and the polar cyano moieties. These groups can also be combined to produce bifunctionalized probes potentially capable of interacting at two distinct sites within the CBR-binding domains. These novel compounds display remarkably high binding affinities for CBRs and are exceptionally potent agonists. A key ligand (27a, AM11245) exhibits exceptionally high potency in both in vitro and in vivo assays and was designated as megagonist, a property attributed to its tight binding profile. By acting both centrally and peripherally, 27a distinguishes itself from our previously reported megagonist AM841, whose functions are restricted to the periphery.

Automated summary

Novel cannabinergic probes have been developed to stabilize cannabinoid receptors through tight binding interactions, exhibiting high binding affinity and potent agonist activity. A key ligand, 27a, displays exceptional megagonist properties, acting centrally and peripherally, distinguishing it from previously reported megagonists.