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Article

Systematic Modification of the Substitution Pattern of the 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Scaffold Enabled the Discovery of New Ligands with High Affinity and Selectivity for the Cannabinoid Type 2 Receptor

by
Claudia Mugnaini
1,*,
Magdalena Kostrzewa
2,
Marta Casini
1,
Poulami Kumar
2,
Valeria Catallo
1,
Marco Allarà
2,
Laura Guastaferro
1,
Antonella Brizzi
1,
Marco Paolino
1,
Andrea Tafi
1,
Christelos Kapatais
1,
Gianluca Giorgi
1,
Federica Vacondio
3,
Marco Mor
3,
Federico Corelli
1 and
Alessia Ligresti
2,*
1
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
2
National Research Council of Italy, Institute of Biomolecular Chemistry, 80078 Pozzuoli, Italy
3
Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(13), 4958; https://doi.org/10.3390/molecules28134958
Submission received: 27 May 2023 / Revised: 13 June 2023 / Accepted: 21 June 2023 / Published: 24 June 2023
(This article belongs to the Special Issue Cannabinoid-Related Compounds for Medical Use)
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Abstract

Selective ligands of the CB2 receptor are receiving considerable attention due to their potential as therapeutic agents for a variety of diseases. Recently, 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide derivatives were shown to act at the CB2 receptor either as agonists or as inverse agonists/antagonists in vitro and to have anti-osteoarthritic activity in vivo. In this article, we report the synthesis, pharmacological profile, and molecular modeling of a series of twenty-three new 7-hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamides with the aim of further developing this new class of selective CB2 ligands. In addition to these compounds, seven other analogs that had been previously synthesized were included in this study to better define the structure–activity relationship (SAR). Ten of the new compounds studied were found to be potent and selective ligands of the CB2 receptor, with Ki values ranging from 48.46 to 0.45 nM and CB1/CB2 selectivity indices (SI) ranging from >206 to >4739. In particular, compounds 54 and 55 were found to be high-affinity CB2 inverse agonists that were not active at all at the CB1 receptor, whereas 57 acted as an agonist. The functional activity profile of the compounds within this structural class depends mainly on the substitution pattern of the pyrazole ring.
Keywords: cannabinoid type-2 ligands; receptor selectivity; structure–activity relationship; pyrazolo[4,3-b]pyridine derivatives cannabinoid type-2 ligands; receptor selectivity; structure–activity relationship; pyrazolo[4,3-b]pyridine derivatives

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MDPI and ACS Style

Mugnaini, C.; Kostrzewa, M.; Casini, M.; Kumar, P.; Catallo, V.; Allarà, M.; Guastaferro, L.; Brizzi, A.; Paolino, M.; Tafi, A.; et al. Systematic Modification of the Substitution Pattern of the 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Scaffold Enabled the Discovery of New Ligands with High Affinity and Selectivity for the Cannabinoid Type 2 Receptor. Molecules 2023, 28, 4958. https://doi.org/10.3390/molecules28134958

AMA Style

Mugnaini C, Kostrzewa M, Casini M, Kumar P, Catallo V, Allarà M, Guastaferro L, Brizzi A, Paolino M, Tafi A, et al. Systematic Modification of the Substitution Pattern of the 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Scaffold Enabled the Discovery of New Ligands with High Affinity and Selectivity for the Cannabinoid Type 2 Receptor. Molecules. 2023; 28(13):4958. https://doi.org/10.3390/molecules28134958

Chicago/Turabian Style

Mugnaini, Claudia, Magdalena Kostrzewa, Marta Casini, Poulami Kumar, Valeria Catallo, Marco Allarà, Laura Guastaferro, Antonella Brizzi, Marco Paolino, Andrea Tafi, and et al. 2023. "Systematic Modification of the Substitution Pattern of the 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Scaffold Enabled the Discovery of New Ligands with High Affinity and Selectivity for the Cannabinoid Type 2 Receptor" Molecules 28, no. 13: 4958. https://doi.org/10.3390/molecules28134958

APA Style

Mugnaini, C., Kostrzewa, M., Casini, M., Kumar, P., Catallo, V., Allarà, M., Guastaferro, L., Brizzi, A., Paolino, M., Tafi, A., Kapatais, C., Giorgi, G., Vacondio, F., Mor, M., Corelli, F., & Ligresti, A. (2023). Systematic Modification of the Substitution Pattern of the 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Scaffold Enabled the Discovery of New Ligands with High Affinity and Selectivity for the Cannabinoid Type 2 Receptor. Molecules, 28(13), 4958. https://doi.org/10.3390/molecules28134958

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