title: Different pharmacological profile of two closely related endocannabinoid ester analogs.
abstract: The pharmacological and neuroprotective properties of two ester analogs of the endocannabinoids, arachidonoylethyleneglycol (AA-EG) and alpha,alpha,-dimethyl arachidonoylethyleneglycol (DMA-EG), were investigated. We examined the interaction of both compounds with cannabinoid receptors (CB1 and CB2) and their efficacy in functional assays. In competition binding assays, AA-EG and DMA-EG had low potency to displace the CB1/CB2 agonist [3H]CP-55,940 in membrane preparations expressing rodent or human receptors. Binding data correlate with low efficacy of both compounds as regards to inhibition of adenylyl cyclase activity. It was also shown that DMA-EG resists hydrolysis by rat brain membranes while AA-EG undergo complete splitting under these conditions. In the cannabinoid tetrad, AA-EG induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating cannabimimetic activity. By contrast, DMA-EG was completely inactive in the same models. DMA-EG and AA-EG potently protected rat cortical neurons in culture against oxygen deprivation at nanomolar concentrations. In glutamate-induced damage, the compounds were less active protecting neurons at micromolar concentrations. The data obtained indicate that the ester endocannabinoid template can be used for the development of new compounds with potent biological activity lacking some of the undesirable behavioral side effects.
authors.affiliation: Laboratory of Oxylipins Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 16/10 Miklukho-Maklaya str., 117437 Moscow, Russia. bobr@oxylipin.ibch.ru
authors.forename: Mikhail
authors.initials: M
authors.lastname: Bobrov
authors.forename: Natalia
authors.initials: N
authors.lastname: Gretskaya
authors.forename: Olivier
authors.initials: O
authors.lastname: Payet
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bezuglov
authors.forename: Thierry
authors.initials: T
authors.lastname: Durand
authors.forename: Laurence
authors.initials: L
authors.lastname: Maurin
authors.forename: Frank
authors.initials: F
authors.lastname: Tourrel
authors.forename: Oumeya
authors.initials: O
authors.lastname: Adjali
authors.forename: Murielle
authors.initials: M
authors.lastname: Rinaldi-Carmona
authors.forename: Agnès
authors.initials: A
authors.lastname: Muller
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001667:Binding, Competitive; D016466:CHO Cells; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003511:Cyclohexanols / Q000378:metabolism; D063388:Endocannabinoids; D005026:Ethylene Glycols / Q000494:pharmacology*; D005260:Female; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; C469526:Cnr2 protein, rat; D003511:Cyclohexanols; D063388:Endocannabinoids; D005026:Ethylene Glycols; D018696:Neuroprotective Agents; D043885:Receptor, Cannabinoid, CB2; C114008:arachidonoylethylene glycol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000242:Cyclic AMP