• Betty B Yao, Gin Hsieh, Anthony V Daza, Yihong Fan, George K Grayson, Tiffany Runyan Garrison, Odile El Kouhen, Bradley A Hooker, Madhavi Pai, Erica J Wensink, Anita K Salyers, Prasant Chandran, Chang Z Zhu, Chengmin Zhong, Keith Ryther, Megan E Gallagher, Chih-Liang Chin, Ann E Tovcimak, Vincent P Hradil, Gerard B Fox, Michael J Dart, Prisca Honore, and Michael D Meyer.
• Neurological Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R47W, AP9A, 100 Abbott Park Road, Abbott Park, IL 60064, USA. betty.yao@abbott.com
• J. Pharmacol. Exp. Ther. 2009 Jan 1;328(1):141-51.

AbstractStudies demonstrating the antihyperalgesic and antiallodynic effects of cannabinoid CB(2) 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 CB(2) 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 CB(2) receptors and selectivity over CB(1) receptors in both human and rat. Likewise, A-836339 exhibits high potencies at CB(2) and selectivity over CB(1) 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 CB(2) receptor-mediated antihyperalgesic effect that is independent of CB(1) or mu-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 CB(1) 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 CB(2) receptor pharmacology and for investigation of the role of CB(2) receptor modulation for treatment of pain in preclinical animal models.

36 keywords...

hide…