Constitutive activity of cannabinoid‐2 (CB2) receptors plays an essential role in the protean agonism of (+)AM1241 and L768242
- 25 August 2009
- journal article
- research article
- Published by Wiley in British Journal of Pharmacology
- Vol. 158 (1), 382-391
- https://doi.org/10.1111/j.1476-5381.2009.00154.x
Abstract
Cannabinoid-2 (CB(2)) receptor-selective agonists have shown anti-nociceptive activity in models of neuropathic and inflammatory pain, and the two agonists most widely used, (+/-)AM1241 [(2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl-methanone] and L768242 [(2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone] (GW405833), have been suggested to be protean agonists. Here we investigated the role of the constitutive activity of CB(2) receptors in (+)AM1241 and L768242 protean agonism. Pharmacological profiles of CB(2) receptor ligands were evaluated in Chinese hamster ovary cells expressing recombinant human (hCB(2)) or rat (rCB(2)) receptors, by measuring modulation of cAMP. To assess the influence of constitutive activity on pharmacological profile, constitutive activity was abolished by pretreatment with AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)], followed by extensive washing. In cell lines expressing either hCB(2) or rCB(2) receptors, (+)AM1241 did not reverse forskolin stimulation of cAMP levels. Conversely, L768242 was an inverse agonist at both hCB(2) and rCB(2) receptors. Abolition of constitutive activity disclosed (+)AM1241 and L768242 agonist activity, while activity of CP55940 [5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol] was unaffected and AM630 became a neutral antagonist. In presence of constitutively active CB(2) receptors, (+)AM1241 antagonized CP55940, but when constitutive activity was abolished, it acted as a partial agonist with additive or antagonistic behaviour, depending on concentration. These results show that (+)AM1241 and L768242 are protean agonists at both hCB(2) and rCB(2) receptors. Abolition of constitutive activity reveals the agonist activity of these compounds. Thus, differences between in vivo and in vitro profiles of CB(2) receptor agonists could be due to different levels of constitutive activity in recombinant versus native CB(2) receptors.Keywords
This publication has 30 references indexed in Scilit:
- Guide to Receptors and Channels (GRAC), 3rd editionBritish Journal of Pharmacology, 2008
- In vitro and in vivo characterization of A‐796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain modelsBritish Journal of Pharmacology, 2008
- Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic painBritish Journal of Pharmacology, 2008
- Species‐specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomersBritish Journal of Pharmacology, 2007
- In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor?British Journal of Pharmacology, 2006
- Agonist-Directed Trafficking of Response by Endocannabinoids Acting at CB2 ReceptorsJournal of Pharmacology and Experimental Therapeutics, 2005
- Evidence for protean agonism of RX 831003 at α2A-adrenoceptors by co-expression with different Gα protein subunitsNeuropharmacology, 2002
- CB2 cannabinoid receptor-mediated peripheral antinociceptionPain, 2001
- Inhibition of Spontaneous β2-Adrenergic Activation Rescues β1-Adrenergic Contractile Response in Cardiomyocytes Overexpressing β2-AdrenoceptorPublished by Elsevier BV ,2000
- Agonist-receptor efficacy II: agonist trafficking of receptor signalsTrends in Pharmacological Sciences, 1995