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

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.