We 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.

Brindisi, M., Maramai, S., Gemma, S., Brogi, S., Grillo, A., Di Cesare Mannelli, L., et al. (2016). Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain. JOURNAL OF MEDICINAL CHEMISTRY, 59(6), 2612-2632 [10.1021/acs.jmedchem.5b01812].

Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain

BRINDISI, MARGHERITA;MARAMAI, SAMUELE;GEMMA, SANDRA;GRILLO, ALESSANDRO;GABELLIERI, EMANUELE;LAMPONI, STEFANIA;SAPONARA, SIMONA;CAMPIANI, GIUSEPPE;BUTINI, STEFANIA
2016-01-01

Abstract

We 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.
Brindisi, M., Maramai, S., Gemma, S., Brogi, S., Grillo, A., Di Cesare Mannelli, L., et al. (2016). Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain. JOURNAL OF MEDICINAL CHEMISTRY, 59(6), 2612-2632 [10.1021/acs.jmedchem.5b01812].
File in questo prodotto:
File Dimensione Formato  
acs.jmedchem.5b01812-2.pdf

non disponibili

Descrizione: Articolo principale
Tipologia: PDF editoriale
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 2.82 MB
Formato Adobe PDF
2.82 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
BUTINI-Development-Post-print-JMC_MGL_revised_16_02_2016.pdf

accesso aperto

Descrizione: DOI: 10.1021/acs.jmedchem.5b01812 J. Med. Chem. 2016, 59, 2612−2632
Tipologia: Post-print
Licenza: PUBBLICO - Pubblico con Copyright
Dimensione 2.67 MB
Formato Adobe PDF
2.67 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/995490