In conclusion a series of new carboxamido aryl isoxazoles wa

In conclusion, a series of new 3-carboxamido-5-aryl-isoxazoles was designed, synthesized and screened for their inhibitory potency against FAAH. Their cytotoxicity was determined and their lipophilicity was calculated. Compounds bearing a 3-substituted biphenyl moiety with high Log values displayed a good inhibitory percentage against FAAH. Compound was identified as a potent FAAH inhibitor devoid of cytotoxicity on HT29 and HEK293 cells. Its good biological activity is probably due to its suitable lipophilicity. This compound possesses a FAAH inhibitory potency comparable to URB597, one of the most potent FAAH inhibitor identified to date. Acknowledgments
Wei TUO is financially supported by China Scholarship Council.
Introduction The endocannabinoid system plays a crucial role in the regulation of neuronal and glial activities. This system comprises of the cannabinoid receptors (CB1 and CB2), their endogenous ligands N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), as well as the enzymes involved in their synthesis and degradation. Fatty HATU mg amide hydrolase (FAAH) is the major degrading enzyme of AEA, therefore pharmacological blockade or genetic deletion of FAAH leads to an increase in AEA levels. Importantly, FAAH hydrolyses a number of important endogenous fatty acid amides, including palmitoylethanolamide (PEA) [1], [2]. AEA is also an endogenous agonist of the transient receptor potential vanilloid 1 (TRPV1) receptor [3], therefore not all the effects of FAAH blockade could be attributed to enhanced CB1 and CB2 receptor signalling. Several lines of evidence suggest that both AEA and PEA are neuroprotective and anti-inflammatory. PEA effectively reduces mast cell-mediated symptoms of inflammation [4], [5], such as edema [6], pain [7] and hyperalgesia [8]. AEA exerts an anti-inflammatory effect on microglia by increasing the expression of CD200R, which is important for the inhibitory neuronal control of microglia [9] and by facilitating the expression of anti-inflammatory cytokines [10]. Treatment with FAAH inhibitors protected neurons against NMDA-induced excitotoxicity in organotypic hippocampal slice cultures [11] and also in vivo in mice with traumatic brain injury [12]. The decreased expression of pro-inflammatory [13], [14] and increased expression of anti-inflammatory mediators in activated microglia suggest that AEA induces a shift of microglial phenotype from M1 to M2 [12]. It was suggested that the neuroprotective effect of AEA is mediated by CB1 and CB2 receptors [15], whereas both cannabinoid receptor dependent [10] and independent [16] effects of AEA on microglial activity were reported. Increased AEA levels were observed in neurodegenerative and neuroinflammatory disorders [17], which is probably neuroprotective, since cannabinoid system activity is thought to be anti-inflammatory and protective in Parkinson disease [18], Alzheimer disease [19], multiple sclerosis [20] and traumatic brain injury [21]. Normal, healthy brain ageing is also associated with an increased number of activated microglia [22], [23], [24] and with an enhanced level of pro-inflammatory cytokines, although the severity of these pro-inflammatory changes is more moderate when compared to neurodegenerative diseases. The increasingly pro-inflammatory environment accelerates brain ageing [25], [26], contributes to cognitive impairments [27], [28] and promotes neurodegeneration [29]. Importantly, the phenotype of microglia changes in ageing. Microglia in the brain of old individuals show activated morphology with bigger cell bodies. They are primed for pro-inflammatory responses and their constitutive release of pro-inflammatory cytokines is enhanced [30]. Astrocytes also undergo functional and morphological changes during ageing: astrocytes in the brain of old animals or humans show enhanced expression of glial fibrillary acidic protein (GFAP) and increased secretion of pro-inflammatory factors [31]. Senescent microglia and astrocytes provide less support for neurons and they are responsible for an enhanced pro-inflammatory microenvironment in the brain, which may contribute to brain ageing.