Gabellieri E

References (3)

Title : Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain - Brindisi_2016_J.Med.Chem_59_2612
Author(s) : Brindisi M , Maramai S , Gemma S , Brogi S , Grillo A , Di Cesare Mannelli L , Gabellieri E , Lamponi S , Saponara S , Gorelli B , Tedesco D , Bonfiglio T , Landry C , Jung KM , Armirotti A , Luongo L , Ligresti A , Piscitelli F , Bertucci C , Dehouck MP , Campiani G , Maione S , Ghelardini C , Pittaluga A , Piomelli D , Di Marzo V , Butini S
Ref : Journal of Medicinal Chemistry , 59 :2612 , 2016
Abstract : We report the discovery of compound 4a, a potent beta-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.
ESTHER : Brindisi_2016_J.Med.Chem_59_2612
PubMedSearch : Brindisi_2016_J.Med.Chem_59_2612
PubMedID: 26888301

Title : Discovery of huperzine A-tacrine hybrids as potent inhibitors of human cholinesterases targeting their midgorge recognition sites - Gemma_2006_J.Med.Chem_49_3421
Author(s) : Gemma S , Gabellieri E , Huleatt P , Fattorusso C , Borriello M , Catalanotti B , Butini S , De Angelis M , Novellino E , Nacci V , Belinskaya T , Saxena A , Campiani G
Ref : Journal of Medicinal Chemistry , 49 :3421 , 2006
Abstract : We describe herein the development of novel huperzine A-tacrine hybrids characterized by 3-methylbicyclo[3.3.1]non-3-ene scaffolds. These compounds were specifically designed to establish tight interactions, through different binding modes, with the midgorge recognition sites of human acetylcholinesterase (hAChE: Y72, D74) and human butyrylcholinesterase (hBuChE: N68, D70) and their catalytic or peripheral sites. Compounds 5a-c show a markedly improved biological profile relative to tacrine and huperzine A.
ESTHER : Gemma_2006_J.Med.Chem_49_3421
PubMedSearch : Gemma_2006_J.Med.Chem_49_3421
PubMedID: 16722663

Title : Conformational flexibility in the peripheral site of Torpedo californica acetylcholinesterase revealed by the complex structure with a bifunctional inhibitor - Colletier_2006_J.Am.Chem.Soc_128_4526
Author(s) : Colletier JP , Sanson B , Nachon F , Gabellieri E , Fattorusso C , Campiani G , Weik M
Ref : Journal of the American Chemical Society , 128 :4526 , 2006
Abstract : The X-ray crystallographic structure of Torpedo californica acetylcholinesterase (TcAChE) in complex with the bifunctional inhibitor NF595, a potentially new anti-Alzheimer drug, has been solved. For the first time in TcAChE, a major conformational change in the peripheral-site tryptophan residue is observed upon complexation. The observed conformational flexibility highlights the dynamic nature of protein structures and is of importance for structure-based drug design.
ESTHER : Colletier_2006_J.Am.Chem.Soc_128_4526
PubMedSearch : Colletier_2006_J.Am.Chem.Soc_128_4526
PubMedID: 16594661
Gene_locus related to this paper: torca-ACHE