C-ring cannabinoid lactones: a novel cannabinergic chemotype

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Organic Synthesis

Background:

• Controlled-deactivation ligands are crucial for drug development.
• Previous work focused on ester groups in tetrahydrocannabinols (THCs).

Purpose of the Study:

• To synthesize and characterize novel THC analogues with a hydrolyzable lactone ring.
• To evaluate the binding affinity and functional activity of these analogues at cannabinoid receptors.
• To investigate the metabolic stability and inactivation pathways of the lead compound.

Main Methods:

• Synthesis of novel seven-membered lactone analogues of THC.
• Radioligand binding assays to determine receptor affinities (CB1, mCB2, hCB2).
• In vitro functional assays to assess receptor agonism.
• Metabolic stability studies using plasma esterases.
• Molecular modeling of lactone structures.

Main Results:

• One synthesized lactone analogue demonstrated high affinity for the CB1 receptor (Ki = 4.6 nM).
• The compound acted as an agonist at the rat CB1 receptor (rCB1).
• The lead lactone was susceptible to metabolic inactivation by plasma esterases, yielding inactive acid metabolites.
• Molecular modeling provided insights into the binding of isomeric lactones.

Conclusions:

• A novel class of cannabinergic lactones with controlled deactivation properties was successfully synthesized.
• The lead compound exhibits potent and selective CB1 agonism with predictable metabolic inactivation.
• These findings offer a promising strategy for developing safer cannabinoid-based therapeutics.