In vivo characterization of the ultrapotent monoacylglycerol lipase inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048)

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

Standard

In vivo characterization of the ultrapotent monoacylglycerol lipase inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048). / Aaltonen, Niina; Kedzierska, Ewa; Orzelska-Górka, Jolanta; Lehtonen, Marko; Navia-Paldanius, Dina; Jakupovic, Hermina; Savinainen, Juha R.; Nevalainen, Tapio; Laitinen, Jarmo T.; Parkkari, Teija; Gynther, Mikko.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 359, No. 1, 10.2016, p. 62-72.

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

Harvard

Aaltonen, N, Kedzierska, E, Orzelska-Górka, J, Lehtonen, M, Navia-Paldanius, D, Jakupovic, H, Savinainen, JR, Nevalainen, T, Laitinen, JT, Parkkari, T & Gynther, M 2016, 'In vivo characterization of the ultrapotent monoacylglycerol lipase inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048)', Journal of Pharmacology and Experimental Therapeutics, vol. 359, no. 1, pp. 62-72. https://doi.org/10.1124/jpet.116.233114

APA

Aaltonen, N., Kedzierska, E., Orzelska-Górka, J., Lehtonen, M., Navia-Paldanius, D., Jakupovic, H., Savinainen, J. R., Nevalainen, T., Laitinen, J. T., Parkkari, T., & Gynther, M. (2016). In vivo characterization of the ultrapotent monoacylglycerol lipase inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048). Journal of Pharmacology and Experimental Therapeutics, 359(1), 62-72. https://doi.org/10.1124/jpet.116.233114

Vancouver

Aaltonen N, Kedzierska E, Orzelska-Górka J, Lehtonen M, Navia-Paldanius D, Jakupovic H et al. In vivo characterization of the ultrapotent monoacylglycerol lipase inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048). Journal of Pharmacology and Experimental Therapeutics. 2016 Oct;359(1):62-72. https://doi.org/10.1124/jpet.116.233114

Author

Aaltonen, Niina ; Kedzierska, Ewa ; Orzelska-Górka, Jolanta ; Lehtonen, Marko ; Navia-Paldanius, Dina ; Jakupovic, Hermina ; Savinainen, Juha R. ; Nevalainen, Tapio ; Laitinen, Jarmo T. ; Parkkari, Teija ; Gynther, Mikko. / In vivo characterization of the ultrapotent monoacylglycerol lipase inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048). In: Journal of Pharmacology and Experimental Therapeutics. 2016 ; Vol. 359, No. 1. pp. 62-72.

Bibtex

@article{ea94a35ebc474b57bca24234381e7807,
title = "In vivo characterization of the ultrapotent monoacylglycerol lipase inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048)",
abstract = "Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048), to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy.",
author = "Niina Aaltonen and Ewa Kedzierska and Jolanta Orzelska-G{\'o}rka and Marko Lehtonen and Dina Navia-Paldanius and Hermina Jakupovic and Savinainen, {Juha R.} and Tapio Nevalainen and Laitinen, {Jarmo T.} and Teija Parkkari and Mikko Gynther",
year = "2016",
month = oct,
doi = "10.1124/jpet.116.233114",
language = "English",
volume = "359",
pages = "62--72",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

RIS

TY - JOUR

T1 - In vivo characterization of the ultrapotent monoacylglycerol lipase inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048)

AU - Aaltonen, Niina

AU - Kedzierska, Ewa

AU - Orzelska-Górka, Jolanta

AU - Lehtonen, Marko

AU - Navia-Paldanius, Dina

AU - Jakupovic, Hermina

AU - Savinainen, Juha R.

AU - Nevalainen, Tapio

AU - Laitinen, Jarmo T.

AU - Parkkari, Teija

AU - Gynther, Mikko

PY - 2016/10

Y1 - 2016/10

N2 - Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048), to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy.

AB - Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048), to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy.

UR - http://www.scopus.com/inward/record.url?scp=84989871077&partnerID=8YFLogxK

U2 - 10.1124/jpet.116.233114

DO - 10.1124/jpet.116.233114

M3 - Journal article

C2 - 27451409

AN - SCOPUS:84989871077

VL - 359

SP - 62

EP - 72

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -

ID: 253189333