4.6 Article

2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties

Journal

PHARMACEUTICALS
Volume 15, Issue 12, Pages -

Publisher

MDPI
DOI: 10.3390/ph15121519

Keywords

dipyrone; metamizole; cannabinoid receptors; CB2 inverse agonists; pyrazolamides; molecular hybridization; NSAID

Funding

  1. Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil (CAPES) [001]
  2. INCT-INOFAR (BR) [465.249/2014-0]
  3. Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) [E-26/010.001273/2016, E-26/202.878/2018, SEI-260003/003613/2022, E-26/202.763/2018, SEI-260003/001182/2020]
  4. Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [304394/2017-3]

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This study investigates the potential mechanism of action of dipyrone and proposes the modulation of cannabinoid receptors CB1 and CB2 as a promising hypothesis. A series of novel pyrazolamides were designed and synthesized with good physicochemical properties and stability. These compounds demonstrated inverse agonist characteristics on CB2 receptors and showed remarkable analgesic activity in a mouse model, suggesting their potential for treating pain syndromes associated with chronic inflammatory diseases.
Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB1 and CB2 appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (7-11) 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 N-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 CB1- or CB2-transfected cells, compounds demonstrated an inverse agonist profile on CB2 receptors and the further characterization of compound LASSBio-2265 (11) revealed moderate binding affinity to CB2 receptor (K-i = 16 mu M) with an EC50 = 0.36 mu M (E-max = 63%). LASSBio-2265 (11) (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.

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