Characterization of a cannabinoid CB2 receptor-selective agonist, A-836339 [2,2,3,3-tetramethyl-cyclopropanecarboxylic acid [3-(2-methoxy-ethyl)-4,5-dimethyl-3H-thiazol-(2Z)-ylidene]-amide], using in vitro pharmacological assays, in vivo pain models, and pharmacological magnetic resonance imaging

  • J Pharmacol Exp Ther. 2009 Jan;328(1):141-51. doi: 10.1124/jpet.108.145011.
Betty B Yao  1 ,  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 ,  Michael D Meyer
Affiliations
  • 1. Neurological Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R47W, AP9A, 100 Abbott Park Road, Abbott Park, IL 60064, USA. [email protected]
PMID: 18931146 DOI: 10.1124/jpet.108.145011
Abstract

Studies 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.

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