RESUMO
The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13 S,1' R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor ( Ki of 7.8 ± 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC50 = 0.6 ± 0.2 nM). (13 S,1' R)-dimethylanandamide is the first potent AEA analogue with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model, 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analogue AM356. This novel analogue will serve as a very useful endocannabinoid probe.
Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Receptor CB1 de Canabinoide/fisiologia , Amidoidrolases/química , Amidoidrolases/metabolismo , Analgésicos/química , Animais , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Estabilidade Enzimática , Adjuvante de Freund/toxicidade , Células HEK293 , Humanos , Hiperalgesia/enzimologia , Inflamação/induzido quimicamente , Inflamação/enzimologia , Lectinas Tipo C/química , Lectinas Tipo C/metabolismo , Masculino , Camundongos , Camundongos Knockout , Monoacilglicerol Lipases/química , Monoacilglicerol Lipases/metabolismo , RatosRESUMO
Two novel methyl-substituted arachidonic acid derivatives were prepared in an enantioselective manner from commercially available chiral building blocks, and were found to be excellent templates for the development of (13S)-methyl-substituted anandamide analogues. One of the compounds synthesized, namely, (13S,5Z,8Z,11Z,14Z)-13-methyl-eicosa-5,8,11,14-tetraenoic acid N-(2-hydroxyethyl)amide, is an endocannabinoid analogue with remarkably high affinity for the CB1 cannabinoid receptor.