Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/6733
DC FieldValueLanguage
dc.contributor.authorBrindisi, Margheritaen_us
dc.contributor.authorMaramai, Samueleen_us
dc.contributor.authorGemma, Sandraen_us
dc.contributor.authorBrogi, Simoneen_us
dc.contributor.authorGrillo, Alessandroen_us
dc.contributor.authorDi Cesare Mannelli, Lorenzoen_us
dc.contributor.authorGabellieri, Emanueleen_us
dc.contributor.authorLamponi, Stefaniaen_us
dc.contributor.authorSaponara, Simonaen_us
dc.contributor.authorGorelli, Beatriceen_us
dc.contributor.authorTedesco, Danieleen_us
dc.contributor.authorBonfiglio, Tommasoen_us
dc.contributor.authorLandry, Christopheen_us
dc.contributor.authorJung, Kwang Mooken_us
dc.contributor.authorArmirotti, Andreaen_us
dc.contributor.authorLuongo, Livioen_us
dc.contributor.authorLigresti, Alessiaen_us
dc.contributor.authorPiscitelli, Fabianaen_us
dc.contributor.authorBertucci, Carloen_us
dc.contributor.authorDehouck, Marie Pierreen_us
dc.contributor.authorCampiani, Giuseppeen_us
dc.contributor.authorMaione, Sabatinoen_us
dc.contributor.authorGhelardini, Carlaen_us
dc.contributor.authorPittaluga, Annaen_us
dc.contributor.authorPiomelli, Danieleen_us
dc.contributor.authorDi Marzo, Vincenzoen_us
dc.contributor.authorButini, Stefaniaen_us
dc.date.accessioned2021-03-30T16:05:28Z-
dc.date.available2021-03-30T16:05:28Z-
dc.date.issued2016-
dc.identifier.issn0022-2623en_US
dc.identifier.urihttp://hdl.handle.net/20.500.12779/6733-
dc.description88768en_US
dc.description.abstractWe report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood-brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity. Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist. Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin. Given these evidence, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.en_US
dc.language.isoenen_US
dc.relationNoneen_US
dc.relation.ispartofJOURNAL OF MEDICINAL CHEMISTRYen_US
dc.subjectAnimals; Arachidonic Acids; Blood-Brain Barrier; Brain; Cell Membrane; Drug Design; Encephalomyelitis, Autoimmune, Experimental; Endocannabinoids; Glycerides; HEK293 Cells; Humans; Mice; Models, Molecular; Monoacylglycerol Lipases; Multiple Sclerosis; Mutagenicity Tests; Neuralgia; Organoplatinum Compounds; Pain; Permeability; Proteomics; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationshipen_US
dc.titleDevelopment and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Painen_US
dc.typeArticleen_US
dc.identifier.doi10.1021/acs.jmedchem.5b01812en_US
dc.identifier.pmid26888301en_US
dc.identifier.scopus2-s2.0-84962198371en_US
dc.identifier.isiWOS:000372946500024en_US
dc.relation.volume59en_US
dc.relation.issue6en_US
dc.description.firstpage2612en_US
dc.description.lastpage2632en_US
dc.description.thirdmissionNot applicableen_US
item.cerifentitytypePublications-
item.grantfulltextnone-
item.languageiso639-1en-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.openairetypeArticle-
item.fulltextNo Fulltext-
crisitem.author.orcid0000-0002-8313-2417-
crisitem.author.orcid0000-0002-2788-8797-
crisitem.author.orcid0000-0001-5295-9529-
crisitem.author.orcid0000-0002-8471-0880-
Appears in Collections:Publications
Show simple item record

Page view(s)

3
Last Week
0
Last month
1
checked on Jun 22, 2021

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.