2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties
Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB<sub>1</sub> and CB<sub>2</sub> appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (<...
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| Format: | Article |
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MDPI AG
2022-12-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/12/1519 |
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| author | Daniela R. de Oliveira Rodolfo C. Maia Patrícia R. de Carvalho França Patrícia D. Fernandes Gisele Barbosa Lídia M. Lima Carlos A. Manssour Fraga |
| author_facet | Daniela R. de Oliveira Rodolfo C. Maia Patrícia R. de Carvalho França Patrícia D. Fernandes Gisele Barbosa Lídia M. Lima Carlos A. Manssour Fraga |
| author_sort | Daniela R. de Oliveira |
| collection | DOAJ |
| description | Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB<sub>1</sub> and CB<sub>2</sub> appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (<b>7</b>–<b>11</b>) designed as molecular hybrids of dipyrone metabolites and NSAIDs, such as ibuprofen and flurbiprofen. Target compounds were obtained in good overall yields (50–80%) by classical amide coupling between 4-aminoantipyrine and arylacetic or arylpropionic acids, followed in some cases by <i>N</i>-methylation of the amide group. The compounds presented good physicochemical properties in addition to stability to chemical (pH 2 and 7.4) and enzymatic (plasma esterases) hydrolysis and showed medium to high gastrointestinal and BBB permeabilities in the PAMPA assay. When subjected to functional testing on CB<sub>1</sub>- or CB<sub>2</sub>-transfected cells, compounds demonstrated an inverse agonist profile on CB<sub>2</sub> receptors and the further characterization of compound LASSBio-2265 (<b>11</b>) revealed moderate binding affinity to CB<sub>2</sub> receptor (K<sub>i</sub> = 16 µM) with an EC<sub>50</sub> = 0.36 µM (E<sub>max</sub> = 63%). LASSBio-2265 (<b>11</b>) (at 1, 3, and 10 mg/kg p.o.) was investigated in the formalin test in mice and a remarkable analgesic activity in the late inflammatory phase was observed, suggesting it could be promising for the treatment of pain syndromes associated with chronic inflammatory diseases. |
| first_indexed | 2024-03-09T15:58:59Z |
| format | Article |
| id | doaj.art-0d9638ca095f4a7cab99181f466a68bc |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T15:58:59Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-0d9638ca095f4a7cab99181f466a68bc2023-11-24T17:16:35ZengMDPI AGPharmaceuticals1424-82472022-12-011512151910.3390/ph151215192-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory PropertiesDaniela R. de Oliveira0Rodolfo C. Maia1Patrícia R. de Carvalho França2Patrícia D. Fernandes3Gisele Barbosa4Lídia M. Lima5Carlos A. Manssour Fraga6Laboratório de Avaliação e Síntese de Substâncias Bioativas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21920-190, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21920-190, RJ, BrazilPrograma de Pós-Graduação em Farmacologia e Química Medicinal, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21920-190, RJ, BrazilPrograma de Pós-Graduação em Farmacologia e Química Medicinal, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21920-190, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21920-190, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21920-190, RJ, BrazilLaboratório de Avaliação e Síntese de Substâncias Bioativas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21920-190, RJ, BrazilAmong the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB<sub>1</sub> and CB<sub>2</sub> appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (<b>7</b>–<b>11</b>) designed as molecular hybrids of dipyrone metabolites and NSAIDs, such as ibuprofen and flurbiprofen. Target compounds were obtained in good overall yields (50–80%) by classical amide coupling between 4-aminoantipyrine and arylacetic or arylpropionic acids, followed in some cases by <i>N</i>-methylation of the amide group. The compounds presented good physicochemical properties in addition to stability to chemical (pH 2 and 7.4) and enzymatic (plasma esterases) hydrolysis and showed medium to high gastrointestinal and BBB permeabilities in the PAMPA assay. When subjected to functional testing on CB<sub>1</sub>- or CB<sub>2</sub>-transfected cells, compounds demonstrated an inverse agonist profile on CB<sub>2</sub> receptors and the further characterization of compound LASSBio-2265 (<b>11</b>) revealed moderate binding affinity to CB<sub>2</sub> receptor (K<sub>i</sub> = 16 µM) with an EC<sub>50</sub> = 0.36 µM (E<sub>max</sub> = 63%). LASSBio-2265 (<b>11</b>) (at 1, 3, and 10 mg/kg p.o.) was investigated in the formalin test in mice and a remarkable analgesic activity in the late inflammatory phase was observed, suggesting it could be promising for the treatment of pain syndromes associated with chronic inflammatory diseases.https://www.mdpi.com/1424-8247/15/12/1519dipyronemetamizolecannabinoid receptorsCB<sub>2</sub> inverse agonistspyrazolamidesmolecular hybridization |
| spellingShingle | Daniela R. de Oliveira Rodolfo C. Maia Patrícia R. de Carvalho França Patrícia D. Fernandes Gisele Barbosa Lídia M. Lima Carlos A. Manssour Fraga 2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties Pharmaceuticals dipyrone metamizole cannabinoid receptors CB<sub>2</sub> inverse agonists pyrazolamides molecular hybridization |
| title | 2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties |
| title_full | 2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties |
| title_fullStr | 2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties |
| title_full_unstemmed | 2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties |
| title_short | 2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties |
| title_sort | 2 arylpropionic acid pyrazolamides as cannabinoid cb2 receptor inverse agonists endowed with anti inflammatory properties |
| topic | dipyrone metamizole cannabinoid receptors CB<sub>2</sub> inverse agonists pyrazolamides molecular hybridization |
| url | https://www.mdpi.com/1424-8247/15/12/1519 |
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