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Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines

Publikation: Bidrag til tidsskriftTidsskriftartikel

  • Riccardo Castelli
  • Laura Scalvini
  • Federica Vacondio
  • Alessio Lodola
  • Mattia Anselmi
  • Stefano Vezzosi
  • Caterina Carmi
  • Michele Bassi
  • Francesca Ferlenghi
  • Silvia Rivara
  • Jennifer Daglian
  • Don Wei
  • Emmanuel Yaw Dotsey
  • Faizy Ahmed
  • Kwang-Mook Jung
  • Nephi Stella
  • Simar Singh
  • Marco Mor
  • Daniele Piomelli

We describe a set of benzisothiazolinone (BTZ) derivatives that are potent inhibitors of monoacylglycerol lipase (MGL), the primary degrading enzyme for the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Structure-activity relationship studies evaluated various substitutions on the nitrogen atom and the benzene ring of the BTZ nucleus. Optimized derivatives with nanomolar potency allowed to investigate the mechanism of MGL inhibition. Site-directed mutagenesis and mass spectrometry experiments showed that BTZs interact in a covalent reversible manner with regulatory cysteines, Cys201 and Cys208, causing a reversible sulfenylation known to modulate MGL activity. Metadynamics simulations revealed that BTZ adducts favor a closed conformation of MGL that occludes substrate recruitment. The BTZ derivative 13 protected neuronal cells from oxidative stimuli and increased 2-AG levels in mouse brain. The results identify Cys201 and Cys208 as key regulators of MGL function, and point to the BTZ scaffold as a useful starting point for the discovery of allosteric MGL inhibitors.

TidsskriftJournal of Medicinal Chemistry
Udgave nummer3
Sider (fra-til)1261-1280
StatusUdgivet - 2020

ID: 230203215