Species comparison and pharmacological characterization of rat and human CB2 cannabinoid receptors.
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.
Mukherjee
Sutapa
S
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
Adams
Monique
M
Whiteaker
Kristi
K
Daza
Anthony
A
Kage
Karen
K
Cassar
Steven
S
Meyer
Michael
M
Yao
Betty Bei
BB
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
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