Jakupovic H

References (2)

Title : 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)m ethanone (JJKK-048) - Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62
Author(s) : Aaltonen N , Kedzierska E , Orzelska-Gorka J , Lehtonen M , Navia-Paldanius D , Jakupovic H , Savinainen JR , Nevalainen T , Laitinen JT , Parkkari T , Gynther M
Ref : Journal of Pharmacology & Experimental Therapeutics , 359 :62 , 2016
Abstract : 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)m ethanone (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.
ESTHER : Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62
PubMedSearch : Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62
PubMedID: 27451409

Title : Chemoproteomic, biochemical and pharmacological approaches in the discovery of inhibitors targeting human alpha\/beta-hydrolase domain containing 11 (ABHD11) - Navia-Paldanius_2016_Eur.J.Pharm.Sci_93_253
Author(s) : Navia-Paldanius D , Patel JZ , Lopez Navarro M , Jakupovic H , Goffart S , Pasonen-Seppanen S , Nevalainen TJ , Jaaskelainen T , Laitinen T , Laitinen JT , Savinainen JR
Ref : Eur J Pharm Sci , 93 :253 , 2016
Abstract : ABHD11 (alpha/beta-hydrolase domain containing 11) is a non-annotated enzyme belonging to the family of metabolic serine hydrolases (mSHs). Its natural substrates and products are unknown. Using competitive activity-based protein profiling (ABPP) to identify novel inhibitors of human (h)ABHD11, three compounds from our chemical library exhibited low nanomolar potency towards hABHD11. Competitive ABPP of various proteomes revealed fatty acid amide hydrolase (FAAH) as the sole off-target among the mSHs. Our fluorescent activity assays designed for natural lipase substrates revealed no activity of hABHD11 towards mono- or diacylglycerols. A broader profiling using para-nitrophenyl (pNP)-linked substrates indicated no amidase/protease, phosphatase, sulfatase, phospholipase C or phosphodiesterase activity. Instead, hABHD11 readily utilized para-nitrophenyl butyrate (pNPC4), indicating lipase/esterase-type activity that could be exploited in inhibitor discovery. Additionally, a homology model was created based on the crystal structure of bacterial esterase YbfF. In contrast to YbfF, which reportedly hydrolyze long-chain acyl-CoA, hABHD11 did not utilize oleoyl-CoA or arachidonoyl-CoA. In conclusion, the present study reports the discovery of potent hABHD11 inhibitors with good selectivity among mSHs. We developed substrate-based activity assays for hABHD11 that could be further exploited in inhibitor discovery and created the first homology-based hABHD11 model, offering initial insights into the active site of this poorly characterized enzyme.
ESTHER : Navia-Paldanius_2016_Eur.J.Pharm.Sci_93_253
PubMedSearch : Navia-Paldanius_2016_Eur.J.Pharm.Sci_93_253
PubMedID: 27544863
Gene_locus related to this paper: human-ABHD11