title: Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor.
abstract: The first endocannabinoid, anandamide, was discovered in 1992. Since then, two other endocannabinoid agonists have been identified, 2-arachidonyl glycerol and, more recently, noladin ether. Here, we report the identification and pharmacological characterization of a novel endocannabinoid, virodhamine, with antagonist properties at the CB1 cannabinoid receptor. Virodhamine is arachidonic acid and ethanolamine joined by an ester linkage. Concentrations of virodhamine measured by liquid chromatography atmospheric pressure chemical ionization-tandem mass spectrometry in rat brain and human hippocampus were similar to anandamide. In peripheral tissues that express the CB2 cannabinoid receptor, virodhamine concentrations were 2- to 9-fold higher than anandamide. In contrast to previously described endocannabinoids, virodhamine was a partial agonist with in vivo antagonist activity at the CB1 receptor. However, at the CB2 receptor, virodhamine acted as a full agonist. Transport of [(14)C]anandamide by RBL-2H3 cells was inhibited by virodhamine. Virodhamine produced hypothermia in the mouse and acted as an antagonist in the presence of anandamide both in vivo and in vitro. As a potential endogenous antagonist at the CB1 receptor, virodhamine adds a new form of regulation to the endocannabinoid system.
authors.affiliation: Lilly Research Laboratories, Neuroscience Division, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Porter
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Knierman
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Becker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Berna
authors.forename: Jingqi
authors.initials: J
authors.lastname: Bao
authors.forename: George G
authors.initials: GG
authors.lastname: Nomikos
authors.forename: Petra
authors.initials: P
authors.lastname: Carter
authors.forename: Frank P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: Andrea Baker
authors.initials: AB
authors.lastname: Leese
authors.forename: Christian C
authors.initials: CC
authors.lastname: Felder
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D019856:Ethanolamine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D053284:Polyunsaturated Alkamides; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C456739:virodhamine; D019856:Ethanolamine; C078814:anandamide