Ogasawara D

References (24)

Title : Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome (NODRS) - Bainbridge_2022_Brain__
Author(s) : Bainbridge MN , Mazumder A , Ogasawara D , Abou Jamra R , Bernard G , Bertini E , Burglen L , Cope H , Crawford A , Derksen A , Dure L , Gantz E , Koch-Hogrebe M , Hurst ACE , Mahida S , Marshall P , Micalizzi A , Novelli A , Peng H , Rodriguez D , Robbins SL , Rutledge SL , Scalise R , Schliesske S , Shashi V , Srivastava S , Thiffault I , Topol S , Qebibo L , Wieczorek D , Cravatt B , Haricharan S , Torkamani A , Friedman J
Ref : Brain , : , 2022
Abstract : The endocannabinoid system is a highly conserved and ubiquitous signaling pathway with broad ranging effects. Despite critical pathway functions, gene variants have not previously been conclusively linked to human disease. We identified nine children from eight families with heterozygous, de novo truncating variants in the last exon of DAGLA with a neuro-ocular phenotype characterized by developmental delay, ataxia, and complex oculomotor abnormality. All children displayed paroxysms of nystagmus or eye deviation accompanied by compensatory head posture and worsened incoordination most frequently after waking. RNAseq showed clear expression of the truncated transcript and no differences were found between mutant and wild type DAGLA activity. Immunofluorescence staining of patient-derived fibroblasts and HEK cells expressing the mutant protein showed distinct perinuclear aggregation not detected in control samples. This report establishes truncating variants in the last DAGLA exon as the cause of a unique pediatric syndrome. Because enzymatic activity was preserved, the observed mis-localization of the truncated protein may account for the observed phenotype. Potential mechanisms include DAGLA haploinsufficiency at the plasma membrane or dominant negative effect. To our knowledge, this is the first report directly linking an endocannabinoid system component with human genetic disease and sets the stage for potential future therapeutic avenues.
ESTHER : Bainbridge_2022_Brain__
PubMedSearch : Bainbridge_2022_Brain__
PubMedID: 35737950
Gene_locus related to this paper: human-DAGLA

Title : A novel monoacylglycerol lipase-targeted (18)F-labeled probe for positron emission tomography imaging of brown adipose tissue in the energy network - Cheng_2022_Acta.Pharmacol.Sin__
Author(s) : Cheng R , Fujinaga M , Yang J , Rong J , Haider A , Ogasawara D , Van RS , Shao T , Chen Z , Zhang X , Calderon Leon ER , Zhang Y , Mori W , Kumata K , Yamasaki T , Xie L , Sun S , Wang L , Ran C , Shao Y , Cravatt B , Josephson L , Zhang MR , Liang SH
Ref : Acta Pharmacol Sin , : , 2022
Abstract : Monoacylglycerol lipase (MAGL) constitutes a serine hydrolase that orchestrates endocannabinoid homeostasis and exerts its function by catalyzing the degradation of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA). As such, selective inhibition of MAGL represents a potential therapeutic and diagnostic approach to various pathologies including neurodegenerative disorders, metabolic diseases and cancers. Based on a unique 4-piperidinyl azetidine diamide scaffold, we developed a reversible and peripheral-specific radiofluorinated MAGL PET ligand [(18)F]FEPAD. Pharmacokinetics and binding studies on [(18)F]FEPAD revealed its outstanding specificity and selectivity towards MAGL in brown adipose tissue (BAT) - a tissue that is known to be metabolically active. We employed [(18)F]FEPAD in PET studies to assess the abundancy of MAGL in BAT deposits of mice and found a remarkable degree of specific tracer binding in the BAT, which was confirmed by post-mortem tissue analysis. Given the negative regulation of endocannabinoids on the metabolic BAT activity, our study supports the concept that dysregulation of MAGL is likely linked to metabolic disorders. Further, we now provide a suitable imaging tool that allows non-invasive assessment of MAGL in BAT deposits, thereby paving the way for detailed mechanistic studies on the role of BAT in endocannabinoid system (ECS)-related pathologies.
ESTHER : Cheng_2022_Acta.Pharmacol.Sin__
PubMedSearch : Cheng_2022_Acta.Pharmacol.Sin__
PubMedID: 35513432
Gene_locus related to this paper: human-MGLL

Title : In situ identification of cellular drug targets in mammalian tissue - Pang_2022_Cell_185_1793
Author(s) : Pang Z , Schafroth MA , Ogasawara D , Wang Y , Nudell V , Lal NK , Yang D , Wang K , Herbst DM , Ha J , Guijas C , Blankman JL , Cravatt BF , Ye L
Ref : Cell , 185 :1793 , 2022
Abstract : The lack of tools to observe drug-target interactions at cellular resolution in intact tissue has been a major barrier to understanding in vivo drug actions. Here, we develop clearing-assisted tissue click chemistry (CATCH) to optically image covalent drug targets in intact mammalian tissues. CATCH permits specific and robust in situ fluorescence imaging of target-bound drug molecules at subcellular resolution and enables the identification of target cell types. Using well-established inhibitors of endocannabinoid hydrolases and monoamine oxidases, direct or competitive CATCH not only reveals distinct anatomical distributions and predominant cell targets of different drug compounds in the mouse brain but also uncovers unexpected differences in drug engagement across and within brain regions, reflecting rare cell types, as well as dose-dependent target shifts across tissue, cellular, and subcellular compartments that are not accessible by conventional methods. CATCH represents a valuable platform for visualizing in vivo interactions of small molecules in tissue.
ESTHER : Pang_2022_Cell_185_1793
PubMedSearch : Pang_2022_Cell_185_1793
PubMedID: 35483372

Title : Positron Emission Tomography Imaging of the Endocannabinoid System: Opportunities and Challenges in Radiotracer Development - Hou_2021_J.Med.Chem_64_123
Author(s) : Hou L , Rong J , Haider A , Ogasawara D , Varlow C , Schafroth MA , Mu L , Gan J , Xu H , Fowler CJ , Zhang MR , Vasdev N , Ametamey S , Cravatt BF , Wang L , Liang SH
Ref : Journal of Medicinal Chemistry , 64 :123 , 2021
Abstract : The endocannabinoid system (ECS) is involved in a wide range of biological functions and comprises cannabinoid receptors and enzymes responsible for endocannabinoid synthesis and degradation. Over the past 2 decades, significant advances toward developing drugs and positron emission tomography (PET) tracers targeting different components of the ECS have been made. Herein, we summarized the recent development of PET tracers for imaging cannabinoid receptors 1 (CB1R) and 2 (CB2R) as well as the key enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), particularly focusing on PET neuroimaging applications. State-of-the-art PET tracers for the ECS will be reviewed including their chemical design, pharmacological properties, radiolabeling, as well as preclinical and human PET imaging. In addition, this review addresses the current challenges for ECS PET biomarker development and highlights the important role of PET ligands to study disease pathophysiology as well as to facilitate drug discovery.
ESTHER : Hou_2021_J.Med.Chem_64_123
PubMedSearch : Hou_2021_J.Med.Chem_64_123
PubMedID: 33379862

Title : Novel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold - Rong_2021_J.Med.Chem__
Author(s) : Rong J , Mori W , Xia X , Schafroth MA , Zhao C , Van RS , Yamasaki T , Chen J , Xiao Z , Haider A , Ogasawara D , Hiraishi A , Shao T , Zhang Y , Chen Z , Pang F , Hu K , Xie L , Fujinaga M , Kumata K , Gou Y , Fang Y , Gu S , Wei H , Bao L , Xu H , Collier TL , Shao Y , Carson RE , Cravatt BF , Wang L , Zhang MR , Liang SH
Ref : Journal of Medicinal Chemistry , : , 2021
Abstract : Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [(18)F]10 and [(18)F]15 ([(18)F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [(18)F]15 demonstrated a better performance. In conclusion, [(18)F]15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.
ESTHER : Rong_2021_J.Med.Chem__
PubMedSearch : Rong_2021_J.Med.Chem__
PubMedID: 34569803
Gene_locus related to this paper: human-MGLL

Title : Development of a highly-specific (18)F-labeled irreversible positron emission tomography tracer for monoacylglycerol lipase mapping - Chen_2021_Acta.Pharm.Sin.B_11_1686
Author(s) : Chen Z , Mori W , Rong J , Schafroth MA , Shao T , Van RS , Ogasawara D , Yamasaki T , Hiraishi A , Hatori A , Chen J , Zhang Y , Hu K , Fujinaga M , Sun J , Yu Q , Collier TL , Shao Y , Cravatt BF , Josephson L , Zhang MR , Liang SH
Ref : Acta Pharm Sin B , 11 :1686 , 2021
Abstract : As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound, which was then radiolabeled with fluorine-18 via a facile S(N)Ar reaction to form 2-[(18)F]fluoropyridine scaffold. Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [(18)F]14 (also named as [(18)F]MAGL-1902). This work may serve as a roadmap for clinical translation and further design of potent (18)F-labeled MAGL PET tracers.
ESTHER : Chen_2021_Acta.Pharm.Sin.B_11_1686
PubMedSearch : Chen_2021_Acta.Pharm.Sin.B_11_1686
PubMedID: 34221877
Gene_locus related to this paper: human-MGLL

Title : Endocannabinoid metabolism and transport as targets to regulate intraocular pressure - Miller_2020_Exp.Eye.Res__108266
Author(s) : Miller S , Daily L , Dharla V , Gertsch J , Malamas MS , Ojima I , Kaczocha M , Ogasawara D , Straiker A
Ref : Experimental Eye Research , :108266 , 2020
Abstract : Cannabinoids are part of an endogenous signaling system found throughout the body, including the eye. Hepler and Frank showed in the early 1970s that plant cannabinoids can lower intraocular pressure (IOP), an effect since shown to occur via cannabinoid CB1 and GPR18 receptors. Endocannabinoids are synthesized and metabolized enzymatically. Enzymes implicated in endocannabinoids breakdown include monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), but also ABHD6, ABHD12, NAAA, and COX-2. Inhibition of MAGL activity raises levels of the endocannabinoid 2-arachidonoyl glycerol and substantially lowers IOP. Blocking other cannabinoid metabolizing enzymes or cannabinoid transporters may similarly contribute to lowering IOP and so serve as therapeutic targets for treating glaucoma. We have tested blockers for several cannabinoid-metabolizing enzymes and transporters (FABP5 and membrane reuptake) for their ability to alter ocular pressure in a murine model of IOP. Of FAAH, ABHD12, NAAA, and COX2, only FAAH was seen to play a role in regulation of IOP. Only the FAAH blocker URB597 lowered IOP, but in a temporally, diurnally, and sex-specific manner. We also tested two blockers of cannabinoid transport (SBFI-26 and WOBE437), finding that each lowered IOP in a CB1-dependent manner. Though we see a modest, limited role for FAAH, our results suggest that MAGL is the primary cannabinoid-metabolizing enzyme in regulating ocular pressure, thus pointing towards a role of 2-arachidonoyl glycerol. Interestingly, inhibition of cannabinoid transport mechanisms independent of hydrolysis may prove to be an alternative strategy to lower ocular pressure.
ESTHER : Miller_2020_Exp.Eye.Res__108266
PubMedSearch : Miller_2020_Exp.Eye.Res__108266
PubMedID: 32979397

Title : Discovery of small-molecule enzyme activators by activity-based protein profiling - Kok_2020_Nat.Chem.Biol_16_997
Author(s) : Kok BP , Ghimire S , Kim W , Chatterjee S , Johns T , Kitamura S , Eberhardt J , Ogasawara D , Xu J , Sukiasyan A , Kim SM , Godio C , Bittencourt JM , Cameron M , Galmozzi A , Forli S , Wolan DW , Cravatt BF , Boger DL , Saez E
Ref : Nat Chemical Biology , 16 :997 , 2020
Abstract : Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse-small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1-a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1's catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.
ESTHER : Kok_2020_Nat.Chem.Biol_16_997
PubMedSearch : Kok_2020_Nat.Chem.Biol_16_997
PubMedID: 32514184
Gene_locus related to this paper: human-LYPLAL1

Title : ABHD12 and LPCAT3 Interplay Regulates a Lyso-phosphatidylserine-C20:4 Phosphatidylserine Lipid Network Implicated in Neurological Disease - Ichu_2020_Biochemistry_59_1793
Author(s) : Ichu TA , Reed A , Ogasawara D , Ulanovskaya O , Roberts A , Aguirre CA , Bar-Peled L , Gao J , Germain J , Barbas S , Masuda K , Conti B , Tontonoz P , Cravatt BF
Ref : Biochemistry , 59 :1793 , 2020
Abstract : PHARC (polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa, and cataract) is a human neurological disorder caused by deleterious mutations in the ABHD12 gene, which encodes an integral membrane lyso-phosphatidylserine (lyso-PS) lipase. Pharmacological or genetic disruption of ABHD12 leads to higher levels of lyso-PS lipids in human cells and the central nervous system (CNS) of mice. ABHD12 loss also causes rapid rewiring of PS content, resulting in selective increases in the level of arachidonoyl (C20:4) PS and decreases in the levels of other PS species. The biochemical basis for ABHD12-dependent PS remodeling and its pathophysiological significance remain unknown. Here, we show that genetic deletion of the lysophospholipid acyltransferase LPCAT3 blocks accumulation of brain C20:4 PS in mice lacking ABHD12 and concurrently produces hyper-increases in the level of lyso-PS in these animals. These lipid changes correlate with exacerbated auditory dysfunction and brain microgliosis in mice lacking both ABHD12 and LPCAT3. Taken together, our findings reveal that ABHD12 and LPCAT3 coordinately regulate lyso-PS and C20:4 PS content in the CNS and point to lyso-PS lipids as the likely bioactive metabolites contributing to PHARC-related neuropathologies.
ESTHER : Ichu_2020_Biochemistry_59_1793
PubMedSearch : Ichu_2020_Biochemistry_59_1793
PubMedID: 32364701
Gene_locus related to this paper: human-ABHD12

Title : Diacylglycerol Lipase-Alpha Regulates Hippocampal-Dependent Learning and Memory Processes in Mice - Schurman_2019_J.Neurosci_39_5949
Author(s) : Schurman LD , Carper MC , Moncayo LV , Ogasawara D , Richardson K , Yu L , Liu X , Poklis JL , Liu QS , Cravatt BF , Lichtman AH
Ref : Journal of Neuroscience , 39 :5949 , 2019
Abstract : Diacylglycerol lipase-alpha (DAGL-alpha), the principal biosynthetic enzyme of the endogenous cannabinoid 2-arachidonylglycerol (2-AG) on neurons, plays a key role in CB(1) receptor-mediated synaptic plasticity and hippocampal neurogenesis, but its contribution to global hippocampal-mediated processes remains unknown. Thus, the present study examines the role that DAGL-alpha plays on LTP in hippocampus, as well as in hippocampal-dependent spatial learning and memory tasks, and on the production of endocannabinoid and related lipids through the use of complementary pharmacologic and genetic approaches to disrupt this enzyme in male mice. Here we show that DAGL-alpha gene deletion or pharmacological inhibition disrupts LTP in CA1 of the hippocampus but elicits varying magnitudes of behavioral learning and memory deficits in mice. In particular, DAGL-alpha(-/-) mice display profound impairments in the Object Location assay and Morris Water Maze (MWM) acquisition engaging in nonspatial search strategies. In contrast, WT mice administered the DAGL-alpha inhibitor DO34 show delays in MWM acquisition and reversal learning, but no deficits in expression, extinction, forgetting, or perseveration processes in this task, as well as no impairment in Object Location. The deficits in synaptic plasticity and MWM performance occur in concert with decreased 2-AG and its major lipid metabolite (arachidonic acid), but increases of a 2-AG diacylglycerol precursor in hippocampus, PFC, striatum, and cerebellum. These novel behavioral and electrophysiological results implicate a direct and perhaps selective role of DAGL-alpha in the integration of new spatial information.SIGNIFICANCE STATEMENT Here we show that genetic deletion or pharmacologic inhibition of diacylglycerol lipase-alpha (DAGL-alpha) impairs hippocampal CA1 LTP, differentially disrupts spatial learning and memory performance in Morris water maze (MWM) and Object Location tasks, and alters brain levels of endocannabinoids and related lipids. Whereas DAGL-alpha(-/-) mice exhibit profound phenotypic spatial memory deficits, a DAGL inhibitor selectively impairs the integration of new information in MWM acquisition and reversal tasks, but not memory processes of expression, extinction, forgetting, or perseveration, and does not affect performance in the Objection Location task. The findings that constitutive or short-term DAGL-alpha disruption impairs learning and memory at electrophysiological and selective in vivo levels implicate this enzyme as playing a key role in the integration of new spatial information.
ESTHER : Schurman_2019_J.Neurosci_39_5949
PubMedSearch : Schurman_2019_J.Neurosci_39_5949
PubMedID: 31127001
Gene_locus related to this paper: mouse-q6wqj1

Title : N-acyl taurines are endogenous lipid messengers that improve glucose homeostasis - Grevengoed_2019_Proc.Natl.Acad.Sci.U.S.A_116_24770
Author(s) : Grevengoed TJ , Trammell SAJ , McKinney MK , Petersen N , Cardone RL , Svenningsen JS , Ogasawara D , Nexoe-Larsen CC , Knop FK , Schwartz TW , Kibbey RG , Cravatt BF , Gillum MP
Ref : Proc Natl Acad Sci U S A , 116 :24770 , 2019
Abstract : Fatty acid amide hydrolase (FAAH) degrades 2 major classes of bioactive fatty acid amides, the N-acylethanolamines (NAEs) and N-acyl taurines (NATs), in central and peripheral tissues. A functional polymorphism in the human FAAH gene is linked to obesity and mice lacking FAAH show altered metabolic states, but whether these phenotypes are caused by elevations in NAEs or NATs is unknown. To overcome the problem of concurrent elevation of NAEs and NATs caused by genetic or pharmacological disruption of FAAH in vivo, we developed an engineered mouse model harboring a single-amino acid substitution in FAAH (S268D) that selectively disrupts NAT, but not NAE, hydrolytic activity. The FAAH-S268D mice accordingly show substantial elevations in NATs without alterations in NAE content, a unique metabolic profile that correlates with heightened insulin sensitivity and GLP-1 secretion. We also show that N-oleoyl taurine (C18:1 NAT), the most abundant NAT in human plasma, decreases food intake, improves glucose tolerance, and stimulates GPR119-dependent GLP-1 and glucagon secretion in mice. Together, these data suggest that NATs act as a class of lipid messengers that improve postprandial glucose regulation and may have potential as investigational metabolites to modify metabolic disease.
ESTHER : Grevengoed_2019_Proc.Natl.Acad.Sci.U.S.A_116_24770
PubMedSearch : Grevengoed_2019_Proc.Natl.Acad.Sci.U.S.A_116_24770
PubMedID: 31740614

Title : Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase alpha\/beta-Hydrolase Domain-Containing 12 (ABHD12) - Ogasawara_2019_J.Med.Chem_62_1643
Author(s) : Ogasawara D , Ichu TA , Jing H , Hulce JJ , Reed A , Ulanovskaya OA , Cravatt BF
Ref : Journal of Medicinal Chemistry , 62 :1643 , 2019
Abstract : ABHD12 is a membrane-bound hydrolytic enzyme that acts on the lysophosphatidylserine (lyso-PS) and lysophosphatidylinositol (lyso-PI) classes of immunomodulatory lipids. Human and mouse genetic studies point to a key role for the ABHD12-(lyso)-PS/PI pathway in regulating (neuro)immunological functions in both the central nervous system and periphery. Selective inhibitors of ABHD12 would offer valuable pharmacological probes to complement genetic models of ABHD12-regulated (lyso)-PS/PI metabolism and signaling. Here, we provide a detailed description of the discovery and activity-based protein profiling (ABPP) guided optimization of reversible thiourea inhibitors of ABHD12 that culminated in the identification of DO264 as a potent, selective, and in vivo active ABHD12 inhibitor. We also show that DO264, but not a structurally related inactive control probe (S)-DO271, augments inflammatory cytokine production from human THP-1 macrophage cells. The in vitro and in vivo properties of DO264 designate this compound as a suitable chemical probe for studying the biological functions of ABHD12-(lyso)-PS/PI pathways.
ESTHER : Ogasawara_2019_J.Med.Chem_62_1643
PubMedSearch : Ogasawara_2019_J.Med.Chem_62_1643
PubMedID: 30720278
Gene_locus related to this paper: human-ABHD12

Title : Design, Synthesis, and Evaluation of (18)F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes - Chen_2019_J.Med.Chem_62_8866
Author(s) : Chen Z , Mori W , Fu H , Schafroth MA , Hatori A , Shao T , Zhang G , Van RS , Zhang Y , Hu K , Fujinaga M , Wang L , Belov V , Ogasawara D , Giffenig P , Deng X , Rong J , Yu Q , Zhang X , Papisov MI , Shao Y , Collier TL , Ma JA , Cravatt BF , Josephson L , Zhang MR , Liang SH
Ref : Journal of Medicinal Chemistry , 62 :8866 , 2019
Abstract : Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. Compound 6 (identified from a therapeutic agent) was advanced for (18)F-labeling via a novel spirocyclic iodonium ylide (SCIDY) strategy, which demonstrated high brain permeability and excellent specific binding. This work supports further development of novel (18)F-labeled MAGL PET probes.
ESTHER : Chen_2019_J.Med.Chem_62_8866
PubMedSearch : Chen_2019_J.Med.Chem_62_8866
PubMedID: 31518130

Title : Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a Tail Switching Strategy on a Piperazinyl Azetidine Skeleton - Chen_2019_J.Med.Chem_62_3336
Author(s) : Chen Z , Mori W , Deng X , Cheng R , Ogasawara D , Zhang G , Schafroth MA , Dahl K , Fu H , Hatori A , Shao T , Zhang Y , Yamasaki T , Zhang X , Rong J , Yu Q , Hu K , Fujinaga M , Xie L , Kumata K , Gou Y , Chen J , Gu S , Bao L , Wang L , Collier TL , Vasdev N , Shao Y , Ma JA , Cravatt BF , Fowler C , Josephson L , Zhang MR , Liang SH
Ref : Journal of Medicinal Chemistry , 62 :3336 , 2019
Abstract : Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with (11)C or (18)F. [(11)C]8 ([(11)C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [(11)C]17 ([(11)C]PAD) and [(18)F]37 ([(18)F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.
ESTHER : Chen_2019_J.Med.Chem_62_3336
PubMedSearch : Chen_2019_J.Med.Chem_62_3336
PubMedID: 30829483
Gene_locus related to this paper: human-MGLL

Title : Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan - Chen_2019_Nat.Chem.Biol_15_453
Author(s) : Chen AL , Lum KM , Lara-Gonzalez P , Ogasawara D , Cognetta AB, 3rd , To A , Parsons WH , Simon GM , Desai A , Petrascheck M , Bar-Peled L , Cravatt BF
Ref : Nat Chemical Biology , 15 :453 , 2019
Abstract : Phenotypic screening has identified small-molecule modulators of aging, but the mechanism of compound action often remains opaque due to the complexities of mapping protein targets in whole organisms. Here, we combine a library of covalent inhibitors with activity-based protein profiling to coordinately discover bioactive compounds and protein targets that extend lifespan in Caenorhabditis elegans. We identify JZL184-an inhibitor of the mammalian endocannabinoid (eCB) hydrolase monoacylglycerol lipase (MAGL or MGLL)-as a potent inducer of longevity, a result that was initially perplexing as C. elegans does not possess an MAGL ortholog. We instead identify FAAH-4 as a principal target of JZL184 and show that this enzyme, despite lacking homology with MAGL, performs the equivalent metabolic function of degrading eCB-related monoacylglycerides in C. elegans. Small-molecule phenotypic screening thus illuminates pure pharmacological connections marking convergent metabolic functions in distantly related organisms, implicating the FAAH-4/monoacylglyceride pathway as a regulator of lifespan in C. elegans.
ESTHER : Chen_2019_Nat.Chem.Biol_15_453
PubMedSearch : Chen_2019_Nat.Chem.Biol_15_453
PubMedID: 30911178

Title : Selective blockade of the lyso-PS lipase ABHD12 stimulates immune responses in vivo - Ogasawara_2018_Nat.Chem.Biol_14_1099
Author(s) : Ogasawara D , Ichu TA , Vartabedian VF , Benthuysen J , Jing H , Reed A , Ulanovskaya OA , Hulce JJ , Roberts A , Brown S , Rosen H , Teijaro JR , Cravatt BF
Ref : Nat Chemical Biology , 14 :1099 , 2018
Abstract : ABHD12 metabolizes bioactive lysophospholipids, including lysophosphatidylserine (lyso-PS). Deleterious mutations in human ABHD12 cause the neurological disease PHARC, and ABHD12(-/-) mice display PHARC-like phenotypes, including hearing loss, along with elevated brain lyso-PS and features of stimulated innate immune cell function. Here, we develop a selective and in vivo-active inhibitor of ABHD12 termed DO264 and show that this compound elevates lyso-PS in mouse brain and primary human macrophages. Unlike ABHD12(-/-) mice, adult mice treated with DO264 exhibited minimal perturbations in auditory function. On the other hand, both DO264-treated and ABHD12(-/-) mice displayed heightened immunological responses to lymphocytic choriomeningitis virus (LCMV) clone 13 infection that manifested as severe lung pathology with elevated proinflammatory chemokines. These results reveal similarities and differences in the phenotypic impact of pharmacological versus genetic blockade of ABHD12 and point to a key role for this enzyme in regulating immunostimulatory lipid pathways in vivo.
ESTHER : Ogasawara_2018_Nat.Chem.Biol_14_1099
PubMedSearch : Ogasawara_2018_Nat.Chem.Biol_14_1099
PubMedID: 30420694
Gene_locus related to this paper: human-ABHD12

Title : In Vitro and in Vivo Evaluation of (11)C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies - Cheng_2018_J.Med.Chem_61_2278
Author(s) : Cheng R , Mori W , Ma L , Alhouayek M , Hatori A , Zhang Y , Ogasawara D , Yuan G , Chen Z , Zhang X , Shi H , Yamasaki T , Xie L , Kumata K , Fujinaga M , Nagai Y , Minamimoto T , Svensson M , Wang L , Du Y , Ondrechen MJ , Vasdev N , Cravatt BF , Fowler C , Zhang MR , Liang SH
Ref : Journal of Medicinal Chemistry , 61 :2278 , 2018
Abstract : Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including (11)C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [(11)C]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.
ESTHER : Cheng_2018_J.Med.Chem_61_2278
PubMedSearch : Cheng_2018_J.Med.Chem_61_2278
PubMedID: 29481079

Title : Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex - McReynolds_2018_Biol.Psychiatry_84_85
Author(s) : McReynolds JR , Doncheck EM , Li Y , Vranjkovic O , Graf EN , Ogasawara D , Cravatt BF , Baker DA , Liu QS , Hillard CJ , Mantsch JR
Ref : Biological Psychiatry , 84 :85 , 2018
Abstract : BACKGROUND: Clinical reports suggest that rather than directly driving cocaine use, stress may create a biological context within which other triggers for drug use become more potent. We hypothesize that stress-induced increases in corticosterone "set the stage" for relapse by promoting endocannabinoid-induced attenuation of inhibitory transmission in the prelimbic cortex (PL). METHODS: We have established a rat model for these stage-setting effects of stress. In this model, neither a stressor (electric footshock) nor stress-level corticosterone treatment alone reinstates cocaine seeking following self-administration and extinction, but each treatment potentiates reinstatement in response to an otherwise subthreshold cocaine priming dose (2.5 mg/kg, intraperitoneal). The contributions of endocannabinoid signaling in the PL to the effects of stress-level corticosterone on PL neurotransmission and cocaine seeking were determined using intra-PL microinfusions. Endocannabinoid-dependent effects of corticosterone on inhibitory synaptic transmission in the rat PL were determined using whole-cell recordings in layer V pyramidal neurons. RESULTS: Corticosterone application attenuated inhibitory synaptic transmission in the PL via cannabinoid receptor type 1 (CB1R)- and 2-arachidonoylglycerol-dependent inhibition of gamma-aminobutyric acid release without altering postsynaptic responses. The ability of systemic stress-level corticosterone treatment to potentiate cocaine-primed reinstatement was recapitulated by intra-PL injection of corticosterone, the CB1R agonist WIN 55,212-2, or the monoacylglycerol lipase inhibitor URB602. Corticosterone effects on reinstatement were attenuated by intra-PL injections of either the CB1R antagonist, AM251, or the diacylglycerol lipase inhibitor, DO34. CONCLUSIONS: These findings suggest that stress-induced increases in corticosterone promote cocaine seeking by mobilizing 2-arachidonoylglycerol in the PL, resulting in CB1R-mediated attenuation of inhibitory transmission in this brain region.
ESTHER : McReynolds_2018_Biol.Psychiatry_84_85
PubMedSearch : McReynolds_2018_Biol.Psychiatry_84_85
PubMedID: 29100630

Title : Investigation of Diacylglycerol Lipase Alpha Inhibition in the Mouse Lipopolysaccharide Inflammatory Pain Model - Wilkerson_2017_J.Pharmacol.Exp.Ther_363_394
Author(s) : Wilkerson JL , Donvito G , Grim TW , Abdullah RA , Ogasawara D , Cravatt BF , Lichtman AH
Ref : Journal of Pharmacology & Experimental Therapeutics , 363 :394 , 2017
Abstract : Diacylglycerol lipase (DAGL) alpha and beta, the major biosynthetic enzymes of the endogenous cannabinoid (endocannabinoid) 2-arachidonylglycerol (2-AG), are highly expressed in the nervous system and immune system, respectively. Genetic deletion or pharmacological inhibition of DAGL-beta protects against lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages and reverses LPS-induced allodynia in mice. To gain insight into the contribution of DAGL-alpha in LPS-induced allodynia, we tested global knockout mice as well as DO34, a dual DAGL-alpha/beta inhibitor. Intraperitoneal administration of DO34 (30 mg/kg) significantly decreased whole-brain levels of 2-AG ( approximately 83%), anandamide ( approximately 42%), and arachidonic acid ( approximately 58%). DO34 dose-dependently reversed mechanical and cold allodynia, and these antinociceptive effects did not undergo tolerance after 6 days of repeated administration. In contrast, DO34 lacked acute thermal antinociceptive, motor, and hypothermal pharmacological effects in naive mice. As previously reported, DAGL-beta (-/-) mice displayed a protective phenotype from LPS-induced allodynia. However, DAGL-alpha (-/-) mice showed full allodynic responses, similar to their wild-type littermates. Interestingly, DO34 (30 mg/kg) fully reversed LPS-induced allodynia in DAGL-alpha (+/+) and (-/-) mice, but did not affect the antinociceptive phenotype of DAGL-beta (-/-) mice in this model, indicating a DAGL-alpha-independent site of action. These findings suggest that DAGL-alpha and DAGL-beta play distinct roles in LPS-induced nociception. Whereas DAGL-alpha appears to be dispensable for the development and expression of LPS-induced nociception, DAGL-beta inhibition represents a promising strategy to treat inflammatory pain.
ESTHER : Wilkerson_2017_J.Pharmacol.Exp.Ther_363_394
PubMedSearch : Wilkerson_2017_J.Pharmacol.Exp.Ther_363_394
PubMedID: 28970359
Gene_locus related to this paper: mouse-q6wqj1

Title : Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding - Deng_2017_J.Med.Chem_60_428
Author(s) : Deng H , Kooijman S , van den Nieuwendijk AM , Ogasawara D , van der Wel T , van Dalen F , Baggelaar MP , Janssen FJ , van den Berg RJ , den Dulk H , Cravatt BF , Overkleeft HS , Rensen PC , van der Stelt M
Ref : Journal of Medicinal Chemistry , 60 :428 , 2017
Abstract : Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2-AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4-substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5-position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting-induced refeeding of mice, thereby emulating the effect of cannabinoid CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets.
ESTHER : Deng_2017_J.Med.Chem_60_428
PubMedSearch : Deng_2017_J.Med.Chem_60_428
PubMedID: 27992221

Title : Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474 - van Esbroeck_2017_Science_356_1084
Author(s) : van Esbroeck ACM , Janssen APA , Cognetta AB, 3rd , Ogasawara D , Shpak G , van der Kroeg M , Kantae V , Baggelaar MP , de Vrij FMS , Deng H , Allara M , Fezza F , Lin Z , van der Wel T , Soethoudt M , Mock ED , den Dulk H , Baak IL , Florea BI , Hendriks G , De Petrocellis L , Overkleeft HS , Hankemeier T , De Zeeuw CI , Di Marzo V , Maccarrone M , Cravatt BF , Kushner SA , van der Stelt M
Ref : Science , 356 :1084 , 2017
Abstract : A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.
ESTHER : van Esbroeck_2017_Science_356_1084
PubMedSearch : van Esbroeck_2017_Science_356_1084
PubMedID: 28596366

Title : A chemical proteomic atlas of brain serine hydrolases identifies cell type-specific pathways regulating neuroinflammation - Viader_2016_Elife_5_
Author(s) : Viader A , Ogasawara D , Joslyn CM , Sanchez-Alavez M , Mori S , Nguyen W , Conti B , Cravatt BF
Ref : Elife , 5 : , 2016
Abstract : Metabolic specialization among major brain cell types is central to nervous system function and determined in large part by the cellular distribution of enzymes. Serine hydrolases are a diverse enzyme class that plays fundamental roles in CNS metabolism and signaling. Here, we perform an activity-based proteomic analysis of primary mouse neurons, astrocytes, and microglia to furnish a global portrait of the cellular anatomy of serine hydrolases in the brain. We uncover compelling evidence for the cellular compartmentalization of key chemical transmission pathways, including the functional segregation of endocannabinoid (eCB) biosynthetic enzymes diacylglycerol lipase-alpha (DAGLalpha) and -beta (DAGLbeta) to neurons and microglia, respectively. Disruption of DAGLbeta perturbed eCB-eicosanoid crosstalk specifically in microglia and suppressed neuroinflammatory events in vivo independently of broader effects on eCB content. Mapping the cellular distribution of metabolic enzymes thus identifies pathways for regulating specialized inflammatory responses in the brain while avoiding global alterations in CNS function.
ESTHER : Viader_2016_Elife_5_
PubMedSearch : Viader_2016_Elife_5_
PubMedID: 26779719

Title : An in vivo multiplexed small-molecule screening platform - Gruner_2016_Nat.Methods_13_883
Author(s) : Gruner BM , Schulze CJ , Yang D , Ogasawara D , Dix MM , Rogers ZN , Chuang CH , McFarland CD , Chiou SH , Brown JM , Cravatt BF , Bogyo M , Winslow MM
Ref : Nat Methods , 13 :883 , 2016
Abstract : Phenotype-based small-molecule screening is a powerful method to identify molecules that regulate cellular functions. However, such screens are generally performed in vitro under conditions that do not necessarily model complex physiological conditions or disease states. Here, we use molecular cell barcoding to enable direct in vivo phenotypic screening of small-molecule libraries. The multiplexed nature of this approach allows rapid in vivo analysis of hundreds to thousands of compounds. Using this platform, we screened >700 covalent inhibitors directed toward hydrolases for their effect on pancreatic cancer metastatic seeding. We identified multiple hits and confirmed the relevant target of one compound as the lipase ABHD6. Pharmacological and genetic studies confirmed the role of this enzyme as a regulator of metastatic fitness. Our results highlight the applicability of this multiplexed screening platform for investigating complex processes in vivo.
ESTHER : Gruner_2016_Nat.Methods_13_883
PubMedSearch : Gruner_2016_Nat.Methods_13_883
PubMedID: 27617390

Title : Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition - Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26
Author(s) : Ogasawara D , Deng H , Viader A , Baggelaar MP , Breman A , den Dulk H , van den Nieuwendijk AM , Soethoudt M , van der Wel T , Zhou J , Overkleeft HS , Sanchez-Alavez M , Mori S , Nguyen W , Conti B , Liu X , Chen Y , Liu QS , Cravatt BF , van der Stelt M
Ref : Proc Natl Acad Sci U S A , 113 :26 , 2016
Abstract : Diacylglycerol lipases (DAGLalpha and DAGLbeta) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLalpha is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network.
ESTHER : Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26
PubMedSearch : Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26
PubMedID: 26668358
Gene_locus related to this paper: human-DAGLA , human-DAGLB