3 research outputs found
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-[(6a<i>R</i>,9<i>R</i>,10a<i>R</i>)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydro-6<i>H</i>-benzoÂ[<i>c</i>]Âchromen-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
Controlled-Deactivation Cannabinergic Ligands
We
report an approach for obtaining novel cannabinoid analogues with
controllable deactivation and improved druggability. Our design involves
the incorporation of a metabolically labile ester group at the 2′-position
on a series of (−)-Δ<sup>8</sup>-THC analogues. We have
sought to introduce benzylic substituents α to the ester group
which affect the half-lives of deactivation through enzymatic activity
while enhancing the affinities and efficacies of individual ligands
for the CB1 and CB2 receptors. The 1′-(<i>S</i>)-methyl,
1′-<i>gem</i>-dimethyl, and 1′-cyclobutyl
analogues exhibit remarkably high affinities for both CB receptors.
The novel ligands are susceptible to enzymatic hydrolysis by plasma
esterases in a controllable manner, while their metabolites are inactive
at the CB receptors. In further in vitro and in vivo experiments key
analogues were shown to be potent CB1 receptor agonists and to exhibit
CB1-mediated hypothermic and analgesic effects
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