de Oliveira Daniela R, Maia Rodolfo C, de Carvalho França Patrícia R, Fernandes Patrícia D, Barbosa Gisele, Lima Lídia M, Fraga Carlos A Manssour
Laboratório de Avaliação e Síntese de Substâncias Bioativas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21920-190, RJ, Brazil.
Programa de Pós-Graduação em Farmacologia e Química Medicinal, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21920-190, RJ, Brazil.
Pharmaceuticals (Basel). 2022 Dec 6;15(12):1519. doi: 10.3390/ph15121519.
Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB and CB appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (-) 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 -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- or CB-transfected cells, compounds demonstrated an inverse agonist profile on CB receptors and the further characterization of compound LASSBio-2265 () revealed moderate binding affinity to CB receptor (K = 16 µM) with an EC = 0.36 µM (E = 63%). LASSBio-2265 () (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.
在最近有关安乃近作用机制的提议中，对大麻素受体CB1和CB2的调节似乎是一个有前景的假说。在此背景下，本研究描述了一系列五种新型吡唑酰胺（-），它们被设计为安乃近代谢物与非甾体抗炎药（如布洛芬和氟比洛芬）的分子杂合体。通过4-氨基安替比林与芳基乙酸或芳基丙酸之间的经典酰胺偶联反应，总体产率良好（50 - 80%），在某些情况下随后对酰胺基团进行N-甲基化，从而得到目标化合物。这些化合物除了对化学（pH 2和7.4）和酶促（血浆酯酶）水解具有稳定性外，还具有良好的物理化学性质，并且在PAMPA试验中显示出中等至高的胃肠道和血脑屏障通透性。当在转染了CB1或CB2的细胞上进行功能测试时，化合物在CB1受体上表现出反向激动剂特征，化合物LASSBio - 2265（）的进一步表征显示其对CB1受体具有中等结合亲和力（K = 16 μM），EC50 = 0.36 μM（Emax = 63%）。在小鼠福尔马林试验中研究了LASSBio - 2265（）（口服剂量为1、3和10 mg/kg），观察到在炎症后期具有显著的镇痛活性，表明其在治疗与慢性炎症性疾病相关的疼痛综合征方面可能具有前景。
