title: Conformationally constrained analogues of 2-arachidonoylglycerol.
abstract: Novel monocyclic analogues of 2-arachidonoylglycerol (2-AG) were designed in order to explore the pharmacophoric conformations of this endocannabinoid ligand at the key cannabinergic proteins. All 2-arachidonoyl esters of 1,2,3-cyclohexanetriol [meso-7 (AM5504), (+/-)-8 (AM5503), and meso-9 (AM5505)] were synthesized by regioselective acylation of 2,3-dihydroxycyclohexanone followed by selective reductions. The optically active isomers (+)-8 (AM4434) and (-)-8 (AM4435) were synthesized from (2S,3S)- and (2R,3R)-2,3-dihydroxycyclohexanone, respectively, via a chemoenzymatic route. These head group constrained and conformationally restricted analogues of 2-AG as well as the 1-keto precursors were evaluated as substrates for the endocannabinoid deactivating hydrolytic enzymes monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), and also were tested for their affinities for CB1 and CB2 cannabinoid receptors. The observed biochemical differences between these ligands can help define the conformational requirements for 2-AG activity at each of the above endocannabinoid protein targets.
authors.affiliation: Center for Drug Discovery, Northeastern University, 116 Mugar Hall, 360 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Subramanian K
authors.initials: SK
authors.lastname: Vadivel
authors.forename: Sundararaman
authors.initials: S
authors.lastname: Vardarajan
authors.forename: Richard I
authors.initials: RI
authors.lastname: Duclos
authors.forename: JodiAnne T
authors.initials: JT
authors.lastname: Wood
authors.forename: Jianxin
authors.initials: J
authors.lastname: Guo
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D001095:Arachidonic Acids / Q000737:chemistry* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D063388:Endocannabinoids; D005989:Glycerides / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects