A Novel Monoacylglycerol Lipase Inhibitor with Analgesic and Anti-inflammatory Activity

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2008 Sep 30

PMID 18819796

Citations 3

Authors

Victoria Magrioti

George Naxakis

Dimitra Hadjipavlou-Litina

Alexandros Makriyannis

George Kokotos

Affiliations

Soon will be listed here.

Abstract

A variety of long chain 1,2-diamines and related compounds were synthesized and tested for their activity on fatty acid amide hydrolase (FAAH) and monoacyglycerol lipase (MGL). (2S,9Z)-Octadec-9-ene-1,2-diamine selectively inhibits MGL (K(i) 21.8 microM) without significantly affecting FAAH. This compound exhibited interesting in vivo analgesic and anti-inflammatory properties, suggesting that selective inhibitors of MGL may be valuable novel agents for the treatment of inflammatory pain.

Citing Articles

Monoacylglycerol lipase - a target for drug development?.

Fowler C Br J Pharmacol. 2012; 166(5):1568-85.

PMID: 22428756 PMC: 3419901. DOI: 10.1111/j.1476-5381.2012.01950.x.

Identification by nuclear magnetic resonance spectroscopy of an active-site hydrogen-bond network in human monoacylglycerol lipase (hMGL): implications for hMGL dynamics, pharmacological inhibition, and catalytic mechanism.

Karageorgos I, Tyukhtenko S, Zvonok N, Janero D, Sallum C, Makriyannis A Mol Biosyst. 2010; 6(8):1381-8.

PMID: 20464001 PMC: 3697746. DOI: 10.1039/c004515b.

The endocannabinoid system and pain.

Guindon J, Hohmann A CNS Neurol Disord Drug Targets. 2009; 8(6):403-21.

PMID: 19839937 PMC: 2834283. DOI: 10.2174/187152709789824660.

References

Vadivel S, Vardarajan S, Duclos Jr R, Wood J, Guo J, Makriyannis A . Conformationally constrained analogues of 2-arachidonoylglycerol. Bioorg Med Chem Lett. 2007; 17(21):5959-63. PMC: 3679891. DOI: 10.1016/j.bmcl.2007.07.064. View

Kokotos G, Verger R, Chiou A . Synthesis of 2-Oxo amide triacylglycerol analogues and study of their inhibition effect on pancreatic and gastric lipases. Chemistry. 2000; 6(22):4211-7. DOI: 10.1002/1521-3765(20001117)6:22<4211::aid-chem4211>3.0.co;2-#. View

Mechoulam R, Hanus L, Ligumsky M, Kaminski N, Schatz A, Gopher A . Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995; 50(1):83-90. DOI: 10.1016/0006-2952(95)00109-d. View

Kokotos G, Six D, Loukas V, Smith T, Constantinou-Kokotou V, Hadjipavlou-Litina D . Inhibition of group IVA cytosolic phospholipase A2 by novel 2-oxoamides in vitro, in cells, and in vivo. J Med Chem. 2004; 47(14):3615-28. DOI: 10.1021/jm030485c. View

Stephens D, Barbayianni E, Constantinou-Kokotou V, Peristeraki A, Six D, Cooper J . Differential inhibition of group IVA and group VIA phospholipases A2 by 2-oxoamides. J Med Chem. 2006; 49(9):2821-8. PMC: 2544624. DOI: 10.1021/jm050993h. View

Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K . 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995; 215(1):89-97. DOI: 10.1006/bbrc.1995.2437. View

Saario S, Palomaki V, Lehtonen M, Nevalainen T, Jarvinen T, Laitinen J . URB754 has no effect on the hydrolysis or signaling capacity of 2-AG in the rat brain. Chem Biol. 2006; 13(8):811-4. DOI: 10.1016/j.chembiol.2006.07.008. View

Lambert D, Fowler C . The endocannabinoid system: drug targets, lead compounds, and potential therapeutic applications. J Med Chem. 2005; 48(16):5059-87. DOI: 10.1021/jm058183t. View

Bisogno T, Cascio M, Saha B, Mahadevan A, Urbani P, Minassi A . Development of the first potent and specific inhibitors of endocannabinoid biosynthesis. Biochim Biophys Acta. 2006; 1761(2):205-12. DOI: 10.1016/j.bbalip.2005.12.009. View

10.

Zvonok N, Pandarinathan L, Williams J, Johnston M, Karageorgos I, Janero D . Covalent inhibitors of human monoacylglycerol lipase: ligand-assisted characterization of the catalytic site by mass spectrometry and mutational analysis. Chem Biol. 2008; 15(8):854-62. PMC: 3972761. DOI: 10.1016/j.chembiol.2008.06.008. View

11.

Romero F, Du W, Hwang I, Rayl T, Kimball F, Leung D . Potent and selective alpha-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase. J Med Chem. 2007; 50(5):1058-68. PMC: 2531193. DOI: 10.1021/jm0611509. View

12.

Tornqvist H, BELFRAGE P . Purification and some properties of a monoacylglycerol-hydrolyzing enzyme of rat adipose tissue. J Biol Chem. 1976; 251(3):813-9. View

13.

Lang W, Qin C, Lin S, Khanolkar A, Goutopoulos A, Fan P . Substrate specificity and stereoselectivity of rat brain microsomal anandamide amidohydrolase. J Med Chem. 1999; 42(5):896-902. DOI: 10.1021/jm980461j. View

14.

Kotsovolou S, Chiou A, Verger R, Kokotos G . Bis-2-oxo amide triacylglycerol analogues: a novel class of potent human gastric lipase inhibitors. J Org Chem. 2001; 66(3):962-7. DOI: 10.1021/jo005705y. View

15.

Di Marzo V, Bifulco M, De Petrocellis L . The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004; 3(9):771-84. DOI: 10.1038/nrd1495. View

16.

Piomelli D . The endocannabinoid system: a drug discovery perspective. Curr Opin Investig Drugs. 2005; 6(7):672-9. View

17.

Makara J, Mor M, Fegley D, Szabo S, Kathuria S, Astarita G . Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat Neurosci. 2005; 8(9):1139-41. DOI: 10.1038/nn1521. View

18.

Cravatt B, Giang D, Mayfield S, Boger D, Lerner R, Gilula N . Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996; 384(6604):83-7. DOI: 10.1038/384083a0. View

19.

Sugiura T, Kodaka T, Nakane S, Miyashita T, Kondo S, Suhara Y . Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds. J Biol Chem. 1999; 274(5):2794-801. DOI: 10.1074/jbc.274.5.2794. View

20.

Stella N, Schweitzer P, Piomelli D . A second endogenous cannabinoid that modulates long-term potentiation. Nature. 1997; 388(6644):773-8. DOI: 10.1038/42015. View