Activation and Binding of Peroxisome Proliferator-Activated Receptor γ by Synthetic Cannabinoid Ajulemic Acid
Abstract
Ajulemic acid (AJA) is a synthetic analog of the tetrahydrocannabinol (THC) metabolite THC-11-oic acid; THC is a major active ingredient of the drug marijuana derived from the plant cannabis. AJA has potent analgesic and anti-inflammatory activity without the psychotropic action of THC. Unlike the nonsteroidal anti-inflammatory drugs, AJA is not ulcerogenic at therapeutic doses, making it a promising anti-inflammatory drug. However, the mechanism of AJA action remains unknown. Here we report that AJA binds directly and specifically to the peroxisome proliferator-activated receptor gamma (PPARgamma), a pharmacologically important member of the nuclear receptor superfamily. Functional assay indicates that AJA activates the transcriptional activity of both human and mouse PPARgamma at pharmacological concentrations. Activation of PPARgamma by AJA requires the AF-2 helix of the receptor, suggesting that AJA activates PPARgamma through the ligand-dependent AF-2 function. AJA binding consistently enables PPARgamma to recruit nuclear receptor coactivators. In addition, we show that AJA inhibits interleukin-8 promoter activity in a PPARgamma-dependent manner, suggesting a link between the anti-inflammatory action of AJA and the activation of PPARgamma. Finally, we find that AJA treatment induces differentiation of 3T3 L1 fibroblasts into adipocytes, a process mediated by PPARgamma. Together, these data indicate that PPARgamma may be a molecular target for AJA, providing a potential mechanism for the anti-inflammatory action of AJA, and possibly other cannabinoids. These studies also implicate other potential therapeutic actions of AJA through PPARgamma activation in multiple signaling pathways.
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CT-3 binds with high affinity to both CB1 and CB2 receptors and also binds with low affinity to PPARγ receptors.
“CT-3 binds with high affinity to both CB1 and CB2 receptors and also binds with low affinity to PPARγ receptors.154”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [154]
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Self-citation
- Authors
- Liu, J., Li, H., Burstein, S. H., Zurier, R. B., & Chen, J. D.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 63
- Issue
- 5
- Pages
- 983-992
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2096073648
- Cited by
- 129
- References
- 54
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 1 · 2022: 9 · 2021: 6 · 2020: 1 · 2019: 8 · 2017: 4 · 2016: 9 · 2015: 3 · 2014: 4 · 2013: 2 · 2012: 7
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- Funders
- National Institutes of Health (5r01da009017-02, 5r01ar038501-13, 5r01da009439-02)
- National Institute on Drug Abuse (DA09017, DA09439)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 52542, R01DK052542, R01DK052888, DK52888)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR38501)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Keywords
- ajulemic acid, PPARγ, synthetic cannabinoids, nuclear receptor ligand binding, transcriptional activation, nuclear receptor coactivators, anti-inflammatory activity, adipogenesis, analgesic activity
- MeSH terms
- Binding Sites, Cell Differentiation, Cells, Cultured, Humans, Promoter Regions, Genetic, Dronabinol, Transcription Factors, Interleukin-8, Adipocytes, Receptors, Cytoplasmic and Nuclear
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