ANXIOLYTIC LIKE PROPERTIES OF ST4070 A NOVEL, POTENT AND SELECTIVE REVERSIBLE INHIBITOR OF FAAH

Introduction: Current management of anxiety, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. Therefore, in the last years an urgent need for novel pharmacological approaches has emerged. One such strategy involves targeting the endocannabinoid system (ECS), and there is now considerable evidence for the central role played by ECS in coping with the regulation of stress and emotions. More recently, attention has moved from directly targeting type-1 cannabinoid (CB1) receptors to indirectly enhancing the content of their endogenous ligands, a more valuable strategy that preserves the spatiotemporal specificity of endocannabinoid activity. Despite recent evidence suggesting the benefits of inhibiting fatty acid amide hydrolase (FAAH), the enzyme that degradates the endogenous CB1 agonist arachidonoylethanolamide (anandamide), further research is needed to demonstrate the therapeutic efficacy of FAAH inhibitors, and their putative translation into the clinic. Methods: ST4070, a novel, potent and selective reversible inhibitor of FAAH, was administered per os in CD1 male mice (3 to 30 mg/10 ml/kg), that were tested in the elevated-plus maze, and in Wistar male rats (3 to 30 mg/2.5 ml/kg), that were tested in the light-dark apparatus. In addition, the effect of ST4070 on FAAH activity and on the content of FAAH substrates (anandamide and palmitoylethanolamide) in selected brain regions was assessed by radiochromatography and LC-MS analysis. Results: ST4070 showed clear anxiolytic-like properties in both rodent models, and in parallel it also produced a clear inhibition of FAAH activity, and a significant increase of anandamide and palmitoylethanolamide in behaviorally-relevant brain regions. Conclusions: Investigation into novel pharmacological targets for the management of anxiety holds the promise to further our understanding of its aetiology, and to develop new and more effective anxiolytic drugs, like the reversible FAAH inhibitor ST4070. [...]