AM2389, a high-affinity, in vivo potent CB1-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice.
The endocannabinoid signaling system (ECS) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies. Current focus is on chemical modifications of the hexahydrocannabinol (HHC) nabilone (Cesamet(®)). To characterize the novel, high-affinity cannabinoid receptor 1 (CB(1)R) HHC-ligand AM2389 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol in two rodent pre-clinical assays. CB(1)R mediation of AM2389-induced hypothermia in mice was evaluated with AM251, a CB(1)R-selective antagonistinverse agonist. Additionally, two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 (0.18 and 0.56 mgkg) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1% saccharinwater. Generalizationsubstitution tests were conducted with AM2389, AM5983, and Δ(9)-tetrahydrocannabinol (Δ(9)-THC). Δ(9)-THC (30 mgkg)-induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 (0.1 and 0.3 mgkg). AM251 (3 and 10 mgkg) attenuatedblocked hypothermia induced by 0.3 mgkg AM2389. In drug discrimination, the order of potency was AM2389 > AM5983 > Δ(9)-THC with ED(50) values of 0.0025, 0.0571, and 0.2635 mgkg, respectively, in the low-dose condition. The corresponding ED(50) values in the high-dose condition were 0.0069, 0.1246, and 0.8438 mgkg, respectively. Onset of the effects of AM2389 was slow with a protracted time-course the functional, perceptual in vivo half-life was approximately 17 h. This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course. The AM2389 chemotype appears well suited for further drug development, and AM2389 currently is used to probe behavioral consequences of sustained ECS activation.