Classical cannabinoids including the plant derived (-)-Δ9-Tetrahydrocannabinol [(-)-Δ9-THC] and its congeners produce their biological effects by modulating the cannabinoid receptors CB1 and CB2. These two GPCR’s are at present being targeted for a variety of conditions such as glaucoma, pain, neurodegeneration, inflammation and eating disorders. However, the application of cannabinoid agonists in therapy has been hampered due to unsought side-effects associated with the CB1 receptor activation as well as poor pharmacokinetic/pharmacodynamics (PK/PD) properties. Thus, the development of safer THC-based medications with favorable oral bioavailability, consistent efficacy, and predictable time course of action remains to be addressed. We recently reported on a controlled deactivation approach where the “soft” drug concept of enzymatic deactivation was combined with a “depot effect” that is frequently observed with Δ9-THC and other hydrophobic cannabinoids. Our earlier generation ligands feature a metabolically labile ester group at strategic positions within the THC structure. In an effort to develop controlled deactivation cannabinoids with faster onset/offset and shorter duration of action than the currently existing THC analogs we have now focused on cannabinergic templates with enhanced polar characteristics that are associated with the depot effect. The novel compounds reported here exhibit high CB receptor binding affinity (Ki = 1-5 nM) and in vitro and in vivo potency and efficacy, and they are susceptible to enzymatic hydrolysis by plasma esterases (t1/2 = 2-10 min) in a controllable manner. Importantly, their hydrolytic metabolites are inactive at CB receptors. In further in vivo experiments involving rodents and non-human primates, one of our second generation analog was found to be a remarkably potent and efficacious CB1 receptor agonist with relatively fast onset/offset to action.

Novel controlled deactivation cannabinoid receptor agonists

251st National Meeting (2016)

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