Unknown

Dataset Information

0

Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol.


ABSTRACT: The pharmacology of monoacylglycerol lipase (MAGL) is not well understood. In consequence, the abilities of a series of analogues of 2-arachidonoylglycerol (2-AG) to inhibit cytosolic 2-oleoylglycerol and membrane-bound anandamide hydolysis by MAGL and fatty acid amide hydrolase (FAAH), respectively, have been investigated. 2-AG and its 1-regioisomer (1-AG) interacted with MAGL with similar affinities (IC(50) values 13 and 17 mum, respectively). Shorter homologues of 2-AG (2-linoleoylglycerol and 2-oleoylglycerol) had affinities for MAGL similar to 2-AG. This pattern was also seen when the arachidonoyl side chain of arachidonoyl trifluoromethylketone was replaced by an oleoyl side chain. Arachidonoyl serinol (IC(50) value 73 microM) was a weaker inhibitor of MAGL than 2-AG. The IC(50) values of noladin ether towards MAGL and FAAH were 36 and 3 microM, respectively. Arachidonoyl glycine interacted with FAAH (IC(50) value 4.9 microM) but only weakly interacted with MAGL (IC(50) value >100 microM). alpha-Methyl-1-AG had similar potencies towards MAGL and FAAH (IC(50) values of 11 and 33 microM, respectively). O-2203 (1-(20-cyano-16,16-dimethyl-eicosa-5,8,11,14-tetraenoyl) glycerol) and O-2204 (2-(20-hydroxy-16,16-dimethyl-eicosa-5,8,11,14-tetraenoyl) glycerol) were slightly less potent, but again affected both enzymes equally. alpha-Methyl-1-AG, O-2203 and O-2204 interacted only weakly with cannabinoid CB(1) receptors expressed in CHO cells (K(i) values 1.8, 3.7 and 3.2 microM, respectively, compared with 0.24 microM for 1-AG) and showed no evidence of central cannabinoid receptor activation in vivo at doses up to 30 mg kg(-1) i.v. It is concluded that compounds like alpha-Methyl-1-AG, O-2203 and O-2204 may be useful as leads for the discovery of selective MAGL inhibitors that lack direct effects upon cannabinoid receptors.

SUBMITTER: Ghafouri N 

PROVIDER: S-EPMC1575926 | biostudies-other | 2004 Nov

REPOSITORIES: biostudies-other

Similar Datasets

| S-EPMC4759315 | biostudies-literature
| S-EPMC3480564 | biostudies-literature
| S-EPMC3382457 | biostudies-literature
| S-EPMC2593629 | biostudies-literature
| S-EPMC8703892 | biostudies-literature
| S-EPMC5792154 | biostudies-other
| S-EPMC2912038 | biostudies-literature
| S-EPMC8306898 | biostudies-literature
2012-02-01 | E-MEXP-3486 | biostudies-arrayexpress
| S-EPMC8158844 | biostudies-literature