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

Abstract

In pursuit of safer controlled-deactivation cannabinoids with high potency and short duration of action, we report the design, synthesis, and pharmacological evaluation of novel C9- and C11-hydroxy-substituted hexahydrocannabinol (HHC) and tetrahydrocannabinol (THC) analogues in which a seven atom long side chain, with or without 1′-substituents, carries a metabolically labile 2′,3′-ester group. Importantly, in vivo studies validated our controlled deactivation approach in rodents and non-human primates. The lead molecule identified here, namely, butyl-2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-3-yl]-2-methylpropanoate (AM7499), was found to exhibit remarkably high in vitro and in vivo potency with shorter duration of action than the currently existing classical cannabinoid agonists.

Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure

“…Third, manipulation of the pharmacokinetic properties of CB 1 receptor agonists could also be helpful for implementation of replacement therapy for cannabis use disorder. For example, the latest efforts to improve the safety and drug-like profiles of CB 1 receptor agonists (Kulkarni et al, 2016b) are directed toward developing controlled-deactivation THC-based analogs that have structures based on THC, but faster onset/ offset and shorter duration of action than currently existing THC analogues. Fourth, certain FAAH inhibitors enhance levels of endogenous cannabinoids but do not have cannabislike rewarding or cognitive effects in animals and could be safe for the treatment of cannabis withdrawal.…”

Controlled-Deactivation CB1 Receptor Ligands as a Novel Strategy to Lower Intraocular Pressure

“…In this regard, the major problem with the currently known classical cannabinoids is their high lipophilicity (e.g., cLogP > 9 for (-)-Δ 8 -THC-DMH, 1 , Figure 1 ), and this needs to be improved while maintaining or enhancing in vivo efficacy. Recently, we reported on a controlled-deactivation approach where the “soft” drug concept of enzymatic deactivation was combined with a “depot effect” which is related to the compound’s lipophilicity as well as its tissue distribution and retention [ 10 , 11 , 12 , 13 ]. Specifically, we have shown that the incorporation of a metabolically labile carboxy ester group (soft spot) at strategic positions within the THC structure leads to potent and efficacious CB1 agonists ( 2 , Figure 1 ) that are bioconverted to inactive metabolites ( 3 ) by plasma esterases.…”

“…Importantly, the rate of hydrolytic cleavage can be accordingly modulated using stereochemical features adjacent to the ester group (enzymatic effect) [ 10 , 11 ]. The depot effect is dependent on the compound’s polar characteristics and can be regulated by varying its log P and polar surface area (PSA) values [ 10 , 11 , 13 ]. This controlled-deactivation approach allowed us to develop novel cannabinoids with a predictable duration of action and an improved druggability, and it is particularly attractive for the design of CB1 activators for ophthalmic use with limited or no psychoactive effects.…”

Synthesis of Functionalized Cannabilactones

“…The design of these analogs was influenced by our earlier SAR work on the C3 side chain of tricyclic tetrahydrocannabinols (THCs) Cannabilactone analogs with modifications at the C9/C11 positions were also prepared in the same manner (Scheme 4). Earlier SAR data indicate that the C9/C11 position of the tricyclic cannabinoids (i.e., THCs, HHCs) is another pharmacophore that can affect the ligand's binding affinity for CB1 and CB2 receptors and pharmacological potency [28,30,31,34]. Thus, in this work, we incorporate various functional groups at C9 of the cannabilactone template, including the hydroxyl and deuterated methoxy groups.…”