Identification and characterization of a new reversible MAGL inhibitor

Tiziano Tuccinardi, Carlotta Granchi, Flavio Rizzolio, Isabella Caligiuri, Vittoria Battistello, Giuseppe Toffoli, Filippo Minutolo, Marco Macchia, Adriano Martinelli

Research output: Contribution to journalArticle

Abstract

Monoacylglycerol lipase is a serine hydrolase that play a major role in the degradation of 2-arachidonoylglycerol, an endocannabinoid neurotransmitter implicated in several physiological processes. Recent studies have shown the possible role of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents. The use of irreversible MAGL inhibitors determined an unwanted chronic MAGL inactivation, which acquires a functional antagonism function of the endocannabinoid system. However, the application of reversible MAGL inhibitors has not yet been explored, mainly due to the scarcity of known compounds possessing efficient reversible inhibitory activities. In this study we reported the first virtual screening analysis for the identification of reversible MAGL inhibitors. Among the screened compounds, the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) is a promising reversible MAGL inhibitor lead (Ki = 8.6 μM), which may be used for the future development of a new class of MAGL inhibitors. Furthermore, the results demonstrate the validity of the methodologies that we followed, encouraging additional screenings of other commercial databases.

Original languageEnglish
Pages (from-to)3285-3291
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number13
DOIs
Publication statusPublished - Jul 1 2014

Fingerprint

Endocannabinoids
Screening
Monoacylglycerol Lipases
Physiological Phenomena
Hydrolases
Reproducibility of Results
Serine
Neurotransmitter Agents
Anti-Inflammatory Agents
Databases
Degradation
Neoplasms
2-arachidonylglycerol
Lead

Keywords

  • Hydrolase
  • MAGL
  • Monoacylglycerol lipase inhibitors
  • Virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

Cite this

Identification and characterization of a new reversible MAGL inhibitor. / Tuccinardi, Tiziano; Granchi, Carlotta; Rizzolio, Flavio; Caligiuri, Isabella; Battistello, Vittoria; Toffoli, Giuseppe; Minutolo, Filippo; Macchia, Marco; Martinelli, Adriano.

In: Bioorganic and Medicinal Chemistry, Vol. 22, No. 13, 01.07.2014, p. 3285-3291.

Research output: Contribution to journalArticle

Tuccinardi, T, Granchi, C, Rizzolio, F, Caligiuri, I, Battistello, V, Toffoli, G, Minutolo, F, Macchia, M & Martinelli, A 2014, 'Identification and characterization of a new reversible MAGL inhibitor', Bioorganic and Medicinal Chemistry, vol. 22, no. 13, pp. 3285-3291. https://doi.org/10.1016/j.bmc.2014.04.057
Tuccinardi, Tiziano ; Granchi, Carlotta ; Rizzolio, Flavio ; Caligiuri, Isabella ; Battistello, Vittoria ; Toffoli, Giuseppe ; Minutolo, Filippo ; Macchia, Marco ; Martinelli, Adriano. / Identification and characterization of a new reversible MAGL inhibitor. In: Bioorganic and Medicinal Chemistry. 2014 ; Vol. 22, No. 13. pp. 3285-3291.
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