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In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects.
Br J Pharmacol. 2014 Mar; 171(6):1392-407.BJ

Abstract

BACKGROUND AND PURPOSE

Since monoacylglycerol lipase (MAGL) has been firmly established as the predominant catabolic enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), a great need has emerged for the development of highly selective MAGL inhibitors. Here, we tested the in vivo effects of one such compound, KML29 (1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate).

EXPERIMENTAL APPROACH

In the present study, we tested KML29 in murine inflammatory (i.e. carrageenan) and sciatic nerve injury pain models, as well as the diclofenac-induced gastric haemorrhage model. KML29 was also evaluated for cannabimimetic effects, including measurements of locomotor activity, body temperature, catalepsy, and cannabinoid interoceptive effects in the drug discrimination paradigm.

KEY RESULTS

KML29 attenuated carrageenan-induced paw oedema and completely reversed carrageenan-induced mechanical allodynia. These effects underwent tolerance after repeated administration of high-dose KML29, which were accompanied by cannabinoid receptor 1 (CB1) receptor desensitization. Acute or repeated KML29 administration increased 2-AG levels and concomitantly reduced arachidonic acid levels, but without elevating anandamide (AEA) levels in the whole brain. Furthermore, KML29 partially reversed allodynia in the sciatic nerve injury model and completely prevented diclofenac-induced gastric haemorrhages. CB1 and CB2 receptors played differential roles in these pharmacological effects of KML29. In contrast, KML29 did not elicit cannabimimetic effects, including catalepsy, hypothermia and hypomotility. Although KML29 did not substitute for Δ(9) -tetrahydrocannabinol (THC) in C57BL/6J mice, it fully and dose-dependantly substituted for AEA in fatty acid amide hydrolase (FAAH) (-/-) mice, consistent with previous work showing that dual FAAH and MAGL inhibition produces THC-like subjective effects.

CONCLUSIONS AND IMPLICATIONS

These results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects.

LINKED ARTICLES

This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23848221

Citation

Ignatowska-Jankowska, B M., et al. "In Vivo Characterization of the Highly Selective Monoacylglycerol Lipase Inhibitor KML29: Antinociceptive Activity Without Cannabimimetic Side Effects." British Journal of Pharmacology, vol. 171, no. 6, 2014, pp. 1392-407.
Ignatowska-Jankowska BM, Ghosh S, Crowe MS, et al. In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. Br J Pharmacol. 2014;171(6):1392-407.
Ignatowska-Jankowska, B. M., Ghosh, S., Crowe, M. S., Kinsey, S. G., Niphakis, M. J., Abdullah, R. A., Tao, Q., O' Neal, S. T., Walentiny, D. M., Wiley, J. L., Cravatt, B. F., & Lichtman, A. H. (2014). In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. British Journal of Pharmacology, 171(6), 1392-407. https://doi.org/10.1111/bph.12298
Ignatowska-Jankowska BM, et al. In Vivo Characterization of the Highly Selective Monoacylglycerol Lipase Inhibitor KML29: Antinociceptive Activity Without Cannabimimetic Side Effects. Br J Pharmacol. 2014;171(6):1392-407. PubMed PMID: 23848221.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. AU - Ignatowska-Jankowska,B M, AU - Ghosh,S, AU - Crowe,M S, AU - Kinsey,S G, AU - Niphakis,M J, AU - Abdullah,R A, AU - Tao,Q, AU - O' Neal,S T, AU - Walentiny,D M, AU - Wiley,J L, AU - Cravatt,B F, AU - Lichtman,A H, PY - 2013/02/04/received PY - 2013/06/14/revised PY - 2013/07/08/accepted PY - 2013/7/16/entrez PY - 2013/7/16/pubmed PY - 2014/11/6/medline KW - 2-arachidonoylglycerol KW - CB1 KW - CB2 KW - allodynia KW - cannabinoid KW - gastric haemorrhage KW - inflammatory pain KW - monoacylglycerol lipase KW - mouse KW - neuropathic pain SP - 1392 EP - 407 JF - British journal of pharmacology JO - Br J Pharmacol VL - 171 IS - 6 N2 - BACKGROUND AND PURPOSE: Since monoacylglycerol lipase (MAGL) has been firmly established as the predominant catabolic enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), a great need has emerged for the development of highly selective MAGL inhibitors. Here, we tested the in vivo effects of one such compound, KML29 (1,1,1,3,3,3-hexafluoropropan-2-yl 4-(bis(benzo[d][1,3]dioxol-5-yl)(hydroxy)methyl)piperidine-1-carboxylate). EXPERIMENTAL APPROACH: In the present study, we tested KML29 in murine inflammatory (i.e. carrageenan) and sciatic nerve injury pain models, as well as the diclofenac-induced gastric haemorrhage model. KML29 was also evaluated for cannabimimetic effects, including measurements of locomotor activity, body temperature, catalepsy, and cannabinoid interoceptive effects in the drug discrimination paradigm. KEY RESULTS: KML29 attenuated carrageenan-induced paw oedema and completely reversed carrageenan-induced mechanical allodynia. These effects underwent tolerance after repeated administration of high-dose KML29, which were accompanied by cannabinoid receptor 1 (CB1) receptor desensitization. Acute or repeated KML29 administration increased 2-AG levels and concomitantly reduced arachidonic acid levels, but without elevating anandamide (AEA) levels in the whole brain. Furthermore, KML29 partially reversed allodynia in the sciatic nerve injury model and completely prevented diclofenac-induced gastric haemorrhages. CB1 and CB2 receptors played differential roles in these pharmacological effects of KML29. In contrast, KML29 did not elicit cannabimimetic effects, including catalepsy, hypothermia and hypomotility. Although KML29 did not substitute for Δ(9) -tetrahydrocannabinol (THC) in C57BL/6J mice, it fully and dose-dependantly substituted for AEA in fatty acid amide hydrolase (FAAH) (-/-) mice, consistent with previous work showing that dual FAAH and MAGL inhibition produces THC-like subjective effects. CONCLUSIONS AND IMPLICATIONS: These results indicate that KML29, a highly selective MAGL inhibitor, reduces inflammatory and neuropathic nociceptive behaviour without occurrence of cannabimimetic side effects. LINKED ARTICLES: This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/23848221/In_vivo_characterization_of_the_highly_selective_monoacylglycerol_lipase_inhibitor_KML29:_antinociceptive_activity_without_cannabimimetic_side_effects_ L2 - https://doi.org/10.1111/bph.12298 DB - PRIME DP - Unbound Medicine ER -