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NEUROPHARMACOLOGY

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

Neurological Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

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.

Address correspondence to: Dr. Betty B. Yao, Neurological Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R47W, AP9A, 100 Abbott Park Road, Abbott Park, IL 60064. E-mail: betty.yao{at}abbott.com