TY - JOUR T1 - Characterization of a Cannabinoid CB<sub>2</sub> Receptor-Selective Agonist, A-836339 [2,2,3,3-Tetramethyl-cyclopropanecarboxylic Acid [3-(2-Methoxy-ethyl)-4,5-dimethyl-3<em>H</em>-thiazol-(2<em>Z</em>)-ylidene]-amide], Using in Vitro Pharmacological Assays, in Vivo Pain Models, and Pharmacological Magnetic Resonance Imaging JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 141 LP - 151 DO - 10.1124/jpet.108.145011 VL - 328 IS - 1 AU - Betty B. Yao AU - Gin Hsieh AU - Anthony V. Daza AU - Yihong Fan AU - George K. Grayson AU - Tiffany Runyan Garrison AU - Odile El Kouhen AU - Bradley A. Hooker AU - Madhavi Pai AU - Erica J. Wensink AU - Anita K. Salyers AU - Prasant Chandran AU - Chang Z. Zhu AU - Chengmin Zhong AU - Keith Ryther AU - Megan E. Gallagher AU - Chih-Liang Chin AU - Ann E. Tovcimak AU - Vincent P. Hradil AU - Gerard B. Fox AU - Michael J. Dart AU - Prisca Honore AU - Michael D. Meyer Y1 - 2009/01/01 UR - http://jpet.aspetjournals.org/content/328/1/141.abstract N2 - Studies demonstrating the antihyperalgesic and antiallodynic effects of cannabinoid CB2 receptor activation have been largely derived from the use of receptor-selective ligands. Here, we report the identification of A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], a potent and selective CB2 agonist as characterized in in vitro pharmacological assays and in in vivo models of pain and central nervous system (CNS) behavior models. In radioligand binding assays, A-836339 displays high affinities at CB2 receptors and selectivity over CB1 receptors in both human and rat. Likewise, A-836339 exhibits high potencies at CB2 and selectivity over CB1 receptors in recombinant fluorescence imaging plate reader and cyclase functional assays. In addition A-836339 exhibits a profile devoid of significant affinity at other G-protein-coupled receptors and ion channels. A-836339 was characterized extensively in various animal pain models. In the complete Freund's adjuvant model of inflammatory pain, A-836339 exhibits a potent CB2 receptor-mediated antihyperalgesic effect that is independent of CB1 or μ-opioid receptors. A-836339 has also demonstrated efficacies in the chronic constrain injury (CCI) model of neuropathic pain, skin incision, and capsaicin-induced secondary mechanical hyperalgesia models. Furthermore, no tolerance was developed in the CCI model after subchronic treatment with A-836339 for 5 days. In assessing CNS effects, A-836339 exhibited a CB1 receptor-mediated decrease of spontaneous locomotor activities at a higher dose, a finding consistent with the CNS activation pattern observed by pharmacological magnetic resonance imaging. These data demonstrate that A-836339 is a useful tool for use of studying CB2 receptor pharmacology and for investigation of the role of CB2 receptor modulation for treatment of pain in preclinical animal models. The American Society for Pharmacology and Experimental Therapeutics ER -