“Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype γ of the peroxisome proliferator-activated receptor (PPARγ) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the γ isotype of human PPAR in complex with ajulemic acid, determined at 2.8-Å resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.”
“AJA (also known as CT-3, IP-751, or 1′,1′-dimethylheptyl-Δ8-tetrahydrocannabinol-11-oic acid) was originally designed based on observations of the metabolic transformations of THC using the metabolite THC-11-oic acid as a template. AJA suppresses neuropathic pain in humans and prevents joint tissue injury in rat models of inflammatory arthritis. In all cases, these effects are observed without producing the motor side effects associated with THC.”
“In summary, our results show that AJA, as well as other THC analogs, in presenting specific binding together with minimal toxicity and good bioavailability may provide useful novel templates for rational drug design aimed at PPARγ regulation.”
