title: Species comparison and pharmacological characterization of rat and human CB2 cannabinoid receptors.
abstract: Pharmacological effects of cannabinoid ligands are thought to be mediated through cannabinoid CB1 and CB2 receptor subtypes. Sequence analysis revealed that rat and human cannabinoid CB2 receptors are divergent and share 81% amino acid homology. Pharmacological analysis of the possible species differences between rat and human cannabinoid CB2 receptors was performed using radioligand binding and functional assays. Pronounced species selectivity at the rat cannabinoid CB2 receptor (50- to 140-fold) was observed with AM-1710 (3-(1,1-Dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo[c]chromen-6-one) and AM-1714 (3-(1,1-Dimethyl-heptyl)-1-9-dihydroxy-benzo[c]chromen-6-one). In contrast, JWH-015 ((2-Methyl-1-propyl-1H-indol-3-yl)-napthalen-1-yl-methanone) was 3- to 10-fold selective at the human cannabinoid CB2 receptor. Endocannabinoid ligands were more human receptor selective. Cannabinoid CB2 receptor antagonist, AM-630 ((6-Iodo-2-methyl-1-(2-morpholin-4-yl-ethyl)-1H-indol-3-yl)-(4-methoxy-phenyl)-methanone) was more potent at the rat receptor in radioligand binding and functional assays than that of the human receptor. The findings of the pharmacological differences between the human and rat cannabinoid CB2 receptors in this study provide critical information for characterizing cannabinoid ligands in in vivo rodent models for drug discovery purpose.
authors.affiliation: Neuroscience Disease Research, Global Pharmaceutical Research and Development, AP9A-3, Abbott Laboratories, 100 Abbott Park Rd, Abbott Park, IL 60064, USA. Sutapa.Mukherjee@abbott.com
authors.forename: Sutapa
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Monique
authors.initials: M
authors.lastname: Adams
authors.forename: Kristi
authors.initials: K
authors.lastname: Whiteaker
authors.forename: Anthony
authors.initials: A
authors.lastname: Daza
authors.forename: Karen
authors.initials: K
authors.lastname: Kage
authors.forename: Steven
authors.initials: S
authors.lastname: Cassar
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer
authors.forename: Betty Bei
authors.initials: BB
authors.lastname: Yao
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003511:Cyclohexanols / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005989:Glycerides / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011869:Radioligand Assay; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014162:Transfection; D014316:Tritium
chemical_list: C500323:3-(1,1-dimethyl-heptyl)-1-9-dihydroxy-benzo(c)chromen-6-one; C500321:3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one; D001095:Arachidonic Acids; D048588:Benzoxazines; D002867:Chromones; D003511:Cyclohexanols; D018076:DNA, Complementary; D063388:Endocannabinoids; D005989:Glycerides; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D014316:Tritium; D005576:Colforsin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C094503:glyceryl 2-arachidonate; D000242:Cyclic AMP; D002118:Calcium; C094023:iodopravadoline; C078814:anandamide; C402944:JHW 015