Cited by 99Cannabis and Cannabinoid ResearchPain Mechanisms and TreatmentsAdenosine and Purinergic Signaling

Characterization of a Cannabinoid CB2 Receptor-Selective Agonist, A-836339 [2,2,3,3-Tetramethyl-cyclopropanecarboxylic Acid [3-(2-Methoxy-ethyl)-4,5-dimethyl-3 H-thiazol-(2 Z)-ylidene]-amide], Using in Vitro Pharmacological Assays, in Vivo Pain Models, and Pharmacological Magnetic Resonance Imaging

Yao, Betty B., Hsieh, Gin, Daza, Anthony V., Fan, Yihong, Grayson, George K., Garrison, Tiffany Runyan, El Kouhen, Odile, Hooker, Bradley A. +15 more·2009·The Journal of Pharmacology and Experimental Therapeutics

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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Crossref · 10.1124/jpet.108.145011

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  • Tolerance failed to develop following repeated administration of the CB2-specific agonist A-836339.

    “Tolerance, a feature which may contribute to loss of analgesic efficacy of currently available analgesics, failed to develop following repeated administration the CB2-specific agonist of A-836339.”
  • CB2 agonists may show therapeutic potential for suppressing neuropathic pain without producing tolerance when administered either alone or as adjuncts to existing treatments.

    “Thus, CB2 agonists may show therapeutic potential for suppressing neuropathic pain without producing tolerance when administered either alone or as adjuncts to exisiting treatments.51”

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Authors
Yao, B. B., Hsieh, G., Daza, A. V., Fan, Y., Grayson, G. K., Garrison, T. R., El Kouhen, O., Hooker, B. A., Pai, M., Wensink, E. J., Salyers, A. K., Chandran, P., Zhu, C. Z., Zhong, C., Ryther, K., Gallagher, M. E., Chin, C.-L., Tovcimak, A. E., Hradil, V. P., Fox, G. B., Dart, M. J., Honore, P., & Meyer, M. D.
Affiliations
Abbott (United States) (US)
Venue
The Journal of Pharmacology and Experimental Therapeutics
Publisher
Elsevier BV
Published
2009-01
Volume
328
Issue
1
Pages
141-151
ISSN
0022-3565 (ISSN-L)
OpenAlex
W2114691708
Cited by
92
References
41
Citations by year
2026: 1 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 7 · 2013: 6 · 2012: 7
FWCI
6.80
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Keywords
antihyperalgesia, antiallodynia, inflammatory pain, neuropathic pain, complete Freund's adjuvant, chronic constriction injury, skin incision, locomotor activity
MeSH terms
Amides, Animals, Cell Line, Cricetulus, Cyclopropanes, Cricetinae, Hindlimb, Humans, Hyperalgesia, Inflammation, Kidney, Magnetic Resonance Imaging, Male, Pain, Postoperative Pain, Pain, Postoperative, Psychomotor Performance, CHO Cells, Rats, Sprague-Dawley, Receptor, Cannabinoid, CB1, Receptor, Cannabinoid, CB2, Rats, Dermatologic Surgical Procedures

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