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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines. / Castelli, Riccardo; Scalvini, Laura; Vacondio, Federica; Lodola, Alessio; Anselmi, Mattia; Vezzosi, Stefano; Carmi, Caterina; Bassi, Michele; Ferlenghi, Francesca; Rivara, Silvia; Möller, Ingvar R; Rand, Kasper D; Daglian, Jennifer; Wei, Don; Dotsey, Emmanuel Yaw; Ahmed, Faizy; Jung, Kwang-Mook; Stella, Nephi; Singh, Simar; Mor, Marco; Piomelli, Daniele.

In: Journal of Medicinal Chemistry, Vol. 63, No. 3, 2020, p. 1261-1280.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Castelli, R, Scalvini, L, Vacondio, F, Lodola, A, Anselmi, M, Vezzosi, S, Carmi, C, Bassi, M, Ferlenghi, F, Rivara, S, Möller, IR, Rand, KD, Daglian, J, Wei, D, Dotsey, EY, Ahmed, F, Jung, K-M, Stella, N, Singh, S, Mor, M & Piomelli, D 2020, 'Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines', Journal of Medicinal Chemistry, vol. 63, no. 3, pp. 1261-1280. https://doi.org/10.1021/acs.jmedchem.9b01679

APA

Castelli, R., Scalvini, L., Vacondio, F., Lodola, A., Anselmi, M., Vezzosi, S., Carmi, C., Bassi, M., Ferlenghi, F., Rivara, S., Möller, I. R., Rand, K. D., Daglian, J., Wei, D., Dotsey, E. Y., Ahmed, F., Jung, K-M., Stella, N., Singh, S., ... Piomelli, D. (2020). Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines. Journal of Medicinal Chemistry, 63(3), 1261-1280. https://doi.org/10.1021/acs.jmedchem.9b01679

Vancouver

Castelli R, Scalvini L, Vacondio F, Lodola A, Anselmi M, Vezzosi S et al. Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines. Journal of Medicinal Chemistry. 2020;63(3):1261-1280. https://doi.org/10.1021/acs.jmedchem.9b01679

Author

Castelli, Riccardo ; Scalvini, Laura ; Vacondio, Federica ; Lodola, Alessio ; Anselmi, Mattia ; Vezzosi, Stefano ; Carmi, Caterina ; Bassi, Michele ; Ferlenghi, Francesca ; Rivara, Silvia ; Möller, Ingvar R ; Rand, Kasper D ; Daglian, Jennifer ; Wei, Don ; Dotsey, Emmanuel Yaw ; Ahmed, Faizy ; Jung, Kwang-Mook ; Stella, Nephi ; Singh, Simar ; Mor, Marco ; Piomelli, Daniele. / Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines. In: Journal of Medicinal Chemistry. 2020 ; Vol. 63, No. 3. pp. 1261-1280.

Bibtex

@article{d3c113958c4c480f98d9d17e64584326,
title = "Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines",
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 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.",
author = "Riccardo Castelli and Laura Scalvini and Federica Vacondio and Alessio Lodola and Mattia Anselmi and Stefano Vezzosi and Caterina Carmi and Michele Bassi and Francesca Ferlenghi and Silvia Rivara and M{\"o}ller, {Ingvar R} and Rand, {Kasper D} and Jennifer Daglian and Don Wei and Dotsey, {Emmanuel Yaw} and Faizy Ahmed and Kwang-Mook Jung and Nephi Stella and Simar Singh and Marco Mor and Daniele Piomelli",
year = "2020",
doi = "10.1021/acs.jmedchem.9b01679",
language = "English",
volume = "63",
pages = "1261--1280",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

RIS

TY - JOUR

T1 - Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines

AU - Castelli, Riccardo

AU - Scalvini, Laura

AU - Vacondio, Federica

AU - Lodola, Alessio

AU - Anselmi, Mattia

AU - Vezzosi, Stefano

AU - Carmi, Caterina

AU - Bassi, Michele

AU - Ferlenghi, Francesca

AU - Rivara, Silvia

AU - Möller, Ingvar R

AU - Rand, Kasper D

AU - Daglian, Jennifer

AU - Wei, Don

AU - Dotsey, Emmanuel Yaw

AU - Ahmed, Faizy

AU - Jung, Kwang-Mook

AU - Stella, Nephi

AU - Singh, Simar

AU - Mor, Marco

AU - Piomelli, Daniele

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.9b01679

DO - 10.1021/acs.jmedchem.9b01679

M3 - Journal article

C2 - 31714779

VL - 63

SP - 1261

EP - 1280

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -

ID: 230203215