Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.
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PMID:Discovery of a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics. 1577 30

Fatty acid amide hydrolase (FAAH) is a serine hydrolase responsible for the degradation of anandamide, an endogenous cannabinoid agonist, and oleamide, a sleep-inducing lipid. Recently, Boger and co-workers reported a potent, selective, and efficacious class of reversible alpha-ketoheterocycle inhibitors of FAAH that produce analgesia in animal models (J. Med. Chem. 2005, 48, 1849-1856; Bioorg. Med. Chem. Lett. 2005, 15, 1423-1428). Key aspects of the structure-activity data are addressed here through computational analysis of FAAH inhibition using Monte Carlo (MC) simulations in conjunction with free energy perturbation (FEP) calculations. The MC/FEP simulations demonstrate that incorporation of pyridine at the C5 position of the 2-keto-oxazole and 2-keto-1,3,4-oxadiazole derivatives significantly enhances binding affinity by formation of a hydrogen-bonded array between the pyridyl nitrogen and Lys142 and Thr236. The results also attribute the activity boost upon substitution of oxazole by oxadiazole to reduced steric interactions in the active site and a lower torsional energy penalty upon binding.
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PMID:Elucidation of fatty acid amide hydrolase inhibition by potent alpha-ketoheterocycle derivatives from Monte Carlo simulations. 1633 87

Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048), to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy.
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PMID:In Vivo Characterization of the Ultrapotent Monoacylglycerol Lipase Inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048). 2745 9