Focusing on the importance of the free phenolic hydroxyl moiety, a family of 23 alkylresorcinol-based compounds were developed and evaluated for their cannabinoid receptor binding properties. The non-symmetrical hexylresorcinol derivative 29 turned out to be a CB2-selective competitive antagonist/inverse agonist endowed with good potency. Both the olivetol- and 5-(2-methyloctan-2-yl)resorcinol-based derivatives 23 and 24 exhibited a significant antinociceptive activity. Interestingly, compound 24 proved to be able to activate both cannabinoid and TRPV1 receptors. Even if cannabinoid receptor subtype selectivity remained a goal only partially achieved, results confirm the validity of the alkylresorcinol nucleus as skeleton for the identification of potent cannabinoid receptor modulators.
To my father Vittorio, without whom this study would never have seen the light.
We thank Mr. Marco Allarà, Endocannabinoid Research Group, for technical help in in vitro assays and Dr. Simone Esposito, Department of DMPK, IRBM, Pomezia (Rome), Italy, for HRMS determinations. Authors from Dipartimento di Biotecnologie, Chimica e Farmacia acknowledge the partial support by MIUR Progetto Dipartimenti di Eccellenza 2018-2022, grant n. L. 232/2016.
- Antinociceptive effect
- Cannabinoid ligands
- Dual ligand
- Transient receptor potential vanilloid type-1 channel