Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity

Antonella Brizzi; Francesca Aiello; Serena Boccella; Maria Grazia Cascio; Luciano De Petrocellis; Maria Frosini; Francesca Gado; Alessia Ligresti; Livio Luongo; Pietro Marini; Claudia Mugnaini; Federica Pessina; Federico Corelli; Sabatino Maione; Clementina Manera; Roger G. Pertwee; Vincenzo Di Marzo

doi:10.1016/j.bmc.2020.115513

Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity

Antonella Brizzi^*, Francesca Aiello, Serena Boccella, Maria Grazia Cascio, Luciano De Petrocellis, Maria Frosini, Francesca Gado, Alessia Ligresti, Livio Luongo, Pietro Marini, Claudia Mugnaini, Federica Pessina, Federico Corelli, Sabatino Maione, Clementina Manera, Roger G. Pertwee, Vincenzo Di Marzo

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

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.

Original language	English
Article number	115513
Number of pages	11
Journal	Bioorganic and Medicinal Chemistry
Volume	28
Issue number	11
Early online date	20 Apr 2020
DOIs	https://doi.org/10.1016/j.bmc.2020.115513
Publication status	Published - 1 Jun 2020

Bibliographical note

Acknowledgments

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.

Keywords

Alkylresorcinols
Antinociceptive effect
Cannabinoid ligands
Dual ligand
Endocannabinoids
Transient receptor potential vanilloid type-1 channel

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Brizzi, A., Aiello, F., Boccella, S., Cascio, M. G., De Petrocellis, L., Frosini, M., Gado, F., Ligresti, A., Luongo, L., Marini, P., Mugnaini, C., Pessina, F., Corelli, F., Maione, S., Manera, C., Pertwee, R. G., & Di Marzo, V. (2020). Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity. Bioorganic and Medicinal Chemistry, 28(11), Article 115513. https://doi.org/10.1016/j.bmc.2020.115513

Brizzi, A, Aiello, F, Boccella, S, Cascio, MG, De Petrocellis, L, Frosini, M, Gado, F, Ligresti, A, Luongo, L, Marini, P, Mugnaini, C, Pessina, F, Corelli, F, Maione, S, Manera, C, Pertwee, RG & Di Marzo, V 2020, 'Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity', Bioorganic and Medicinal Chemistry, vol. 28, no. 11, 115513. https://doi.org/10.1016/j.bmc.2020.115513

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abstract = "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.",

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AU - Cascio, Maria Grazia

AU - De Petrocellis, Luciano

AU - Frosini, Maria

AU - Gado, Francesca

AU - Ligresti, Alessia

AU - Luongo, Livio

AU - Marini, Pietro

AU - Mugnaini, Claudia

AU - Pessina, Federica

AU - Corelli, Federico

AU - Maione, Sabatino

AU - Manera, Clementina

AU - Pertwee, Roger G.

AU - Di Marzo, Vincenzo

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N2 - 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.

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Synthetic bioactive olivetol-related amides: The influence of the phenolic group in cannabinoid receptor activity

Abstract

Bibliographical note

Keywords

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