1. Academic Validation
  2. Benzisothiazolinone Derivatives as Potent Allosteric Monoacylglycerol Lipase Inhibitors That Functionally Mimic Sulfenylation of Regulatory Cysteines

Benzisothiazolinone Derivatives as Potent Allosteric Monoacylglycerol Lipase Inhibitors That Functionally Mimic Sulfenylation of Regulatory Cysteines

  • J Med Chem. 2020 Feb 13;63(3):1261-1280. doi: 10.1021/acs.jmedchem.9b01679.
Riccardo Castelli 1 Laura Scalvini 1 Federica Vacondio 1 2 Alessio Lodola 1 Mattia Anselmi 1 Stefano Vezzosi 1 Caterina Carmi 1 Michele Bassi 1 Francesca Ferlenghi 1 2 Silvia Rivara 1 2 Ingvar R Møller 3 Kasper D Rand 3 Jennifer Daglian Don Wei Emmanuel Y Dotsey Faizy Ahmed Kwang-Mook Jung Nephi Stella 4 Simar Singh 4 Marco Mor 1 2 Daniele Piomelli
Affiliations

Affiliations

  • 1 Dipartimento di Scienze degli Alimenti e del Farmaco , Università degli Studi di Parma , Parco Area delle Scienze 27/A , I-43124 Parma , Italy.
  • 2 Centro Interdipartimentale Biopharmanet-tec , Università degli Studi di Parma, Parco Area delle Scienze , Tecnopolo Padiglione 33 , I-43124 Parma , Italy.
  • 3 Department of Pharmacy , Universitetsparken 2 , DK-2100 Copenhagen , Denmark.
  • 4 Department of Pharmacology, Psychiatry and Behavioral Sciences , University of Washington , Seattle , Washington 98195-7280 , United States.
Abstract

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 us 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 the 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.

Figures