1 research outputs found
Probing the Carboxyester Side Chain in Controlled Deactivation (−)‑Δ<sup>8</sup>‑Tetrahydrocannabinols
We
recently reported on a controlled deactivation/detoxification approach
for obtaining cannabinoids with improved druggability. Our design
incorporates a metabolically labile ester group at strategic positions
within the THC structure. We have now synthesized a series of (−)-Δ<sup>8</sup>-THC analogues encompassing a carboxyester group within the
3-alkyl chain in an effort to explore this novel cannabinergic chemotype
for CB receptor binding affinity, in vitro and in vivo potency and
efficacy, as well as controlled deactivation by plasma esterases.
We have also probed the chain’s polar characteristics with
regard to fast onset and short duration of action. Our lead molecule,
namely 2-[(6a<i>R</i>,10a<i>R</i>)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6,9-trimethyl-6<i>H</i>-dibenzoÂ[<i>b</i>,<i>d</i>]Âpyran-3-yl]-2-methyl-propanoic
acid 3-cyano-propyl ester (AM7438), showed picomolar affinity for
CB receptors and is deactivated by plasma esterases while the respective
acid metabolite is inactive. In further in vitro and in vivo experiments,
the compound was found to be a remarkably potent and efficacious CB1
receptor agonist with relatively fast onset/offset of action