title: Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1).
abstract: Two subtypes of the cannabinoid receptor (CB1 and CB2) are expressed in mammalian tissues. Although selective antagonists are available for each of the subtypes, most of the available cannabinoid agonists bind to both CB1 and CB2 with similar affinities. We have synthesized two analogs of N-arachidonylethanolamine (AEA), arachidonylcyclopropylamide (ACPA) and arachidonyl-2-chloroethylamide (ACEA), that bind to the CB1 receptor with very high affinity (KI values of 2.2 +/- 0.4 nM and 1.4 +/- 0.3 nM, respectively) and to the CB2 receptor with low affinity (KI values of 0.7 +/- 0.01 microM and 3.1 +/- 1.0 microM, respectively). Both ACPA and ACEA have the characteristics of agonists at the CB1 receptor; both inhibit forskolin-induced accumulation of cAMP in Chinese hamster ovary cells expressing the human CB1 receptor, and both analogs increase the binding of [35S]GTPgammaS to cerebellar membranes and inhibit electrically evoked contractions of the mouse vas deferens. ACPA and ACEA produce hypothermia in mice, and this effect is inhibited by coadministration of the CB1 receptor antagonist SR141716A. Therefore, ACPA and ACEA are high-affinity agonists of the CB1 receptor but do not bind the CB2 receptor, suggesting that structural analogs of AEA can be designed with considerable selectivity for the CB1 receptor over the CB2 receptor.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Hillard
authors.forename: S
authors.initials: S
authors.lastname: Manna
authors.forename: M J
authors.initials: MJ
authors.lastname: Greenberg
authors.forename: R
authors.initials: R
authors.lastname: DiCamelli
authors.forename: R A
authors.initials: RA
authors.lastname: Ross
authors.forename: L A
authors.initials: LA
authors.lastname: Stevenson
authors.forename: V
authors.initials: V
authors.lastname: Murphy
authors.forename: R G
authors.initials: RG
authors.lastname: Pertwee
authors.forename: W B
authors.initials: WB
authors.lastname: Campbell
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D016466:CHO Cells; D002186:Cannabinoids / Q000494:pharmacology; D002531:Cerebellum / Q000502:physiology*; D006224:Cricetinae; D003511:Cyclohexanols / Q000494:pharmacology; D004558:Electric Stimulation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000502:physiology*; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D014162:Transfection; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D002186:Cannabinoids; D003511:Cyclohexanols; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D011994:Recombinant Proteins; C119325:arachidonyl-2-chloroethylamide; C119324:arachidonylcyclopropylamide; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000262:Adenylyl Cyclases