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

被引：68

作者：

Yao, Betty B. ^{[1
]}

Hsieh, Gin ^{[1
]}

Daza, Anthony V. ^{[1
]}

Fan, Yihong ^{[1
]}

Grayson, George K. ^{[1
]}

Garrison, Tiffany Runyan ^{[1
]}

El Kouhen, Odile ^{[1
]}

Hooker, Bradley A. ^{[1
]}

Pai, Madhavi ^{[1
]}

Wensink, Erica J. ^{[1
]}

Salyers, Anita K. ^{[1
]}

Chandran, Prasant ^{[1
]}

Zhu, Chang Z. ^{[1
]}

Zhong, Chengmin ^{[1
]}

Ryther, Keith ^{[1
]}

Gallagher, Megan E. ^{[1
]}

Chin, Chih-Liang ^{[1
]}

Tovcimak, Ann E. ^{[1
]}

Hradil, Vincent P. ^{[1
]}

Fox, Gerard B. ^{[1
]}

Dart, Michael J. ^{[1
]}

Honore, Prisca ^{[1
]}

Meyer, Michael D. ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Neurol Dis Res, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS | 2009年 / 328卷 / 01期

关键词：

NEUROPATHIC PAIN; ENDOGENOUS OPIOIDS; INFLAMMATORY PAIN; ADENYLYL-CYCLASE; RAT; ACTIVATION; EXPRESSION; ANTINOCICEPTION; HYPERALGESIA; INDUCTION;

D O I：

10.1124/jpet.108.145011

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 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 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.

引用

页码：141 / 151

页数：11