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A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence
Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a pe...
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Published in: | Nature communications 2023-12, Vol.14 (1), p.8039-19, Article 8039 |
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container_title | Nature communications |
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creator | Jiang, Ming Huizenga, Mirjam C. W. Wirt, Jonah L. Paloczi, Janos Amedi, Avand van den Berg, Richard J. B. H. N. Benz, Joerg Collin, Ludovic Deng, Hui Di, Xinyu Driever, Wouter F. Florea, Bogdan I. Grether, Uwe Janssen, Antonius P. A. Hankemeier, Thomas Heitman, Laura H. Lam, Tsang-Wai Mohr, Florian Pavlovic, Anto Ruf, Iris van den Hurk, Helma Stevens, Anna F. van der Vliet, Daan van der Wel, Tom Wittwer, Matthias B. van Boeckel, Constant A. A. Pacher, Pal Hohmann, Andrea G. van der Stelt, Mario |
description | Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl
4
-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB
1
activation. Antinociceptive efficacy of LEI-515 was blocked by CB
2
, but not CB
1
, antagonists. The CB
1
antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.
Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence. |
doi_str_mv | 10.1038/s41467-023-43606-3 |
format | article |
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4
-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB
1
activation. Antinociceptive efficacy of LEI-515 was blocked by CB
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, antagonists. The CB
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antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.
Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/s41467-023-43606-3</identifier><identifier>PMID: 38052772</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 2-Arachidonoylglycerol ; 49/98 ; 631/154/309 ; 631/92/436 ; 64/60 ; 692/4017 ; 82/29 ; 82/47 ; 82/51 ; Analgesics ; Analgesics - pharmacology ; Animals ; Antagonists ; Cannabinoid CB1 receptors ; Cannabinoid CB2 receptors ; Carbon tetrachloride ; Central nervous system ; Chemotherapy ; Effectiveness ; Endocannabinoids ; High-throughput screening ; Humanities and Social Sciences ; Inflammation ; Inhibitors ; Lipase ; Liver ; Mice ; Mice, Inbred C57BL ; Monoacylglycerol Lipases ; Monoglycerides ; multidisciplinary ; Necrosis ; Nervous system ; Oxidative stress ; Pain perception ; Peripheral neuropathy ; Receptor, Cannabinoid, CB1 ; Rimonabant ; Science ; Science (multidisciplinary) ; Side effects</subject><ispartof>Nature communications, 2023-12, Vol.14 (1), p.8039-19, Article 8039</ispartof><rights>The Author(s) 2023</rights><rights>2023. The Author(s).</rights><rights>The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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W.</creatorcontrib><creatorcontrib>Wirt, Jonah L.</creatorcontrib><creatorcontrib>Paloczi, Janos</creatorcontrib><creatorcontrib>Amedi, Avand</creatorcontrib><creatorcontrib>van den Berg, Richard J. B. H. N.</creatorcontrib><creatorcontrib>Benz, Joerg</creatorcontrib><creatorcontrib>Collin, Ludovic</creatorcontrib><creatorcontrib>Deng, Hui</creatorcontrib><creatorcontrib>Di, Xinyu</creatorcontrib><creatorcontrib>Driever, Wouter F.</creatorcontrib><creatorcontrib>Florea, Bogdan I.</creatorcontrib><creatorcontrib>Grether, Uwe</creatorcontrib><creatorcontrib>Janssen, Antonius P. 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A.</creatorcontrib><creatorcontrib>Pacher, Pal</creatorcontrib><creatorcontrib>Hohmann, Andrea G.</creatorcontrib><creatorcontrib>van der Stelt, Mario</creatorcontrib><title>A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl
4
-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB
1
activation. Antinociceptive efficacy of LEI-515 was blocked by CB
2
, but not CB
1
, antagonists. The CB
1
antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.
Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence.</description><subject>13</subject><subject>2-Arachidonoylglycerol</subject><subject>49/98</subject><subject>631/154/309</subject><subject>631/92/436</subject><subject>64/60</subject><subject>692/4017</subject><subject>82/29</subject><subject>82/47</subject><subject>82/51</subject><subject>Analgesics</subject><subject>Analgesics - pharmacology</subject><subject>Animals</subject><subject>Antagonists</subject><subject>Cannabinoid CB1 receptors</subject><subject>Cannabinoid CB2 receptors</subject><subject>Carbon tetrachloride</subject><subject>Central nervous system</subject><subject>Chemotherapy</subject><subject>Effectiveness</subject><subject>Endocannabinoids</subject><subject>High-throughput screening</subject><subject>Humanities and Social Sciences</subject><subject>Inflammation</subject><subject>Inhibitors</subject><subject>Lipase</subject><subject>Liver</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Monoacylglycerol Lipases</subject><subject>Monoglycerides</subject><subject>multidisciplinary</subject><subject>Necrosis</subject><subject>Nervous system</subject><subject>Oxidative stress</subject><subject>Pain perception</subject><subject>Peripheral neuropathy</subject><subject>Receptor, Cannabinoid, CB1</subject><subject>Rimonabant</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Side effects</subject><issn>2041-1723</issn><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp9kUGP1SAUhRujcSbj_AEXhsSNmypwgbbLycTRSSZxo2tC4fIeL22p0Gby_r2813E0LmQDge8ezsmpqreMfmQU2k9ZMKGamnKoBSiqanhRXXIqWM0aDi__Ol9U1zkfaFnQsVaI19UFtFTypuGXVb4hY5yiscdhNxwtpjiQIcwmIwnTPvRhiYnkfXwM044se0xmxnUJlqD3wZaxgpExWCSPYdnHdSEWpyWZgeTg8EShXTIpIg5nnBxOFt9Ur7wZMl4_7VfVj7vP32-_1g_fvtzf3jzUVhSvteCd65FyFAx75D03nVLCAtBiXghllXSNsF5SAO99y0so1YDsjHQlu4Wr6n7TddEc9JzCaNJRRxP0-SKmnTapZBlQe9dzDpK7nvYCoela2zLRWd4pCUb6ovVh05pT_LliXvQYssVhMBPGNWvedm0nGy6hoO__QQ9xTVNJeqaYAg6iUHyjbIo5J_TPBhnVp4b11rAuDetzw_ok_e5Jeu1HdM8jv_ssAGxALk_TDtOfv_8j-wtZPrBI</recordid><startdate>20231205</startdate><enddate>20231205</enddate><creator>Jiang, Ming</creator><creator>Huizenga, Mirjam C. 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W. ; Wirt, Jonah L. ; Paloczi, Janos ; Amedi, Avand ; van den Berg, Richard J. B. H. N. ; Benz, Joerg ; Collin, Ludovic ; Deng, Hui ; Di, Xinyu ; Driever, Wouter F. ; Florea, Bogdan I. ; Grether, Uwe ; Janssen, Antonius P. A. ; Hankemeier, Thomas ; Heitman, Laura H. ; Lam, Tsang-Wai ; Mohr, Florian ; Pavlovic, Anto ; Ruf, Iris ; van den Hurk, Helma ; Stevens, Anna F. ; van der Vliet, Daan ; van der Wel, Tom ; Wittwer, Matthias B. ; van Boeckel, Constant A. 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A.</creatorcontrib><creatorcontrib>Pacher, Pal</creatorcontrib><creatorcontrib>Hohmann, Andrea G.</creatorcontrib><creatorcontrib>van der Stelt, Mario</creatorcontrib><collection>SpringerOpen (Open Access)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Environment Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Biological Science Database</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest Publicly Available Content database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Directory of Open Access Journals</collection><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jiang, Ming</au><au>Huizenga, Mirjam C. W.</au><au>Wirt, Jonah L.</au><au>Paloczi, Janos</au><au>Amedi, Avand</au><au>van den Berg, Richard J. B. H. N.</au><au>Benz, Joerg</au><au>Collin, Ludovic</au><au>Deng, Hui</au><au>Di, Xinyu</au><au>Driever, Wouter F.</au><au>Florea, Bogdan I.</au><au>Grether, Uwe</au><au>Janssen, Antonius P. A.</au><au>Hankemeier, Thomas</au><au>Heitman, Laura H.</au><au>Lam, Tsang-Wai</au><au>Mohr, Florian</au><au>Pavlovic, Anto</au><au>Ruf, Iris</au><au>van den Hurk, Helma</au><au>Stevens, Anna F.</au><au>van der Vliet, Daan</au><au>van der Wel, Tom</au><au>Wittwer, Matthias B.</au><au>van Boeckel, Constant A. A.</au><au>Pacher, Pal</au><au>Hohmann, Andrea G.</au><au>van der Stelt, Mario</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2023-12-05</date><risdate>2023</risdate><volume>14</volume><issue>1</issue><spage>8039</spage><epage>19</epage><pages>8039-19</pages><artnum>8039</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl
4
-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB
1
activation. Antinociceptive efficacy of LEI-515 was blocked by CB
2
, but not CB
1
, antagonists. The CB
1
antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.
Chemotherapy-induced peripheral neuropathy (CIPN) represents a major reason for discontinuation of treatment. Here, the authors show that LEI-515, a peripherally restricted monoacylglycerol lipase inhibitor, suppresses CIPN without inducing central nervous system side effects or physical dependence.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>38052772</pmid><doi>10.1038/s41467-023-43606-3</doi><tpages>19</tpages><orcidid>https://orcid.org/0000-0002-7691-4138</orcidid><orcidid>https://orcid.org/0000-0002-3164-9270</orcidid><orcidid>https://orcid.org/0000-0003-1359-4795</orcidid><orcidid>https://orcid.org/0000-0001-5746-6678</orcidid><orcidid>https://orcid.org/0000-0001-7036-8108</orcidid><orcidid>https://orcid.org/0000-0002-6688-4377</orcidid><orcidid>https://orcid.org/0000-0002-1029-5717</orcidid><orcidid>https://orcid.org/0000-0001-7317-9679</orcidid><orcidid>https://orcid.org/0000-0003-4203-261X</orcidid><orcidid>https://orcid.org/0000-0002-1381-8464</orcidid><orcidid>https://orcid.org/0000-0003-0941-6435</orcidid><orcidid>https://orcid.org/0000-0002-6449-3233</orcidid><orcidid>https://orcid.org/0000-0001-8313-0019</orcidid><orcidid>https://orcid.org/0000-0002-9250-0381</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 2041-1723 |
ispartof | Nature communications, 2023-12, Vol.14 (1), p.8039-19, Article 8039 |
issn | 2041-1723 2041-1723 |
language | eng |
recordid | cdi_doaj_primary_oai_doaj_org_article_fdb22352db0b4e3798c8149c29653a5f |
source | Nature Publishing Group; PubMed Central database; Springer Nature - nature.com Journals - Fully Open Access; ProQuest Publicly Available Content database |
subjects | 13 2-Arachidonoylglycerol 49/98 631/154/309 631/92/436 64/60 692/4017 82/29 82/47 82/51 Analgesics Analgesics - pharmacology Animals Antagonists Cannabinoid CB1 receptors Cannabinoid CB2 receptors Carbon tetrachloride Central nervous system Chemotherapy Effectiveness Endocannabinoids High-throughput screening Humanities and Social Sciences Inflammation Inhibitors Lipase Liver Mice Mice, Inbred C57BL Monoacylglycerol Lipases Monoglycerides multidisciplinary Necrosis Nervous system Oxidative stress Pain perception Peripheral neuropathy Receptor, Cannabinoid, CB1 Rimonabant Science Science (multidisciplinary) Side effects |
title | A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence |
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