Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB2Receptor Derived from the Natural Product Cannabidiol

Gemma Navarro; Angel Gonzalez; Adrià Sánchez-Morales; Nil Casajuana-Martin; Marc Gómez-Ventura; Arnau Cordomí; Félix Busqué; Ramon Alibés; Leonardo Pardo; Rafael Franco

doi:10.1021/acs.jmedchem.1c00561

Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB₂Receptor Derived from the Natural Product Cannabidiol

Gemma Navarro, Angel Gonzalez, Adrià Sánchez-Morales, Nil Casajuana-Martin, Marc Gómez-Ventura, Arnau Cordomí, Félix Busqué, Ramon Alibés, Leonardo Pardo, Rafael Franco^*

^*Corresponding author for this work

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

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Abstract

Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility.

Original language	English
Pages (from-to)	9354-9364
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	13
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00561
Publication status	Published - 8 Jul 2021

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Navarro, G., Gonzalez, A., Sánchez-Morales, A., Casajuana-Martin, N., Gómez-Ventura, M., Cordomí, A., Busqué, F., Alibés, R., Pardo, L., & Franco, R. (2021). Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB₂Receptor Derived from the Natural Product Cannabidiol. Journal of Medicinal Chemistry, 64(13), 9354-9364. https://doi.org/10.1021/acs.jmedchem.1c00561

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title = "Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB2Receptor Derived from the Natural Product Cannabidiol",

abstract = "Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility.",

author = "Gemma Navarro and Angel Gonzalez and Adri{\`a} S{\'a}nchez-Morales and Nil Casajuana-Martin and Marc G{\'o}mez-Ventura and Arnau Cordom{\'i} and F{\'e}lix Busqu{\'e} and Ramon Alib{\'e}s and Leonardo Pardo and Rafael Franco",

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year = "2021",

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doi = "10.1021/acs.jmedchem.1c00561",

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Navarro, G, Gonzalez, A, Sánchez-Morales, A, Casajuana-Martin, N, Gómez-Ventura, M, Cordomí, A , Busqué, F , Alibés, R , Pardo, L & Franco, R 2021, 'Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB₂Receptor Derived from the Natural Product Cannabidiol', Journal of Medicinal Chemistry, vol. 64, no. 13, pp. 9354-9364. https://doi.org/10.1021/acs.jmedchem.1c00561

TY - JOUR

T1 - Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB2Receptor Derived from the Natural Product Cannabidiol

AU - Navarro, Gemma

AU - Gonzalez, Angel

AU - Sánchez-Morales, Adrià

AU - Casajuana-Martin, Nil

AU - Gómez-Ventura, Marc

AU - Cordomí, Arnau

AU - Busqué, Félix

AU - Alibés, Ramon

AU - Pardo, Leonardo

AU - Franco, Rafael

PY - 2021/7/8

Y1 - 2021/7/8

N2 - Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility.

AB - Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility.

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U2 - 10.1021/acs.jmedchem.1c00561

DO - 10.1021/acs.jmedchem.1c00561

M3 - Article

C2 - 34161090

AN - SCOPUS:85110110692

SN - 0022-2623

VL - 64

SP - 9354

EP - 9364

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -

Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB₂Receptor Derived from the Natural Product Cannabidiol

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