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Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma.

Ambrosio ALB, Dias SMG, Polikarpov I, Zurier RB, Burstein SH, Garratt RC
J Biol Chem 282 18625-18633 (2007)
Cited: 35 times
EuropePMC logo PMID: 17462987

Abstract

Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype gamma of the peroxisome proliferator-activated receptor (PPARgamma) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the gamma isotype of human PPAR in complex with ajulemic acid, determined at 2.8-A resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.

Reviews - 2om9 mentioned but not cited (1)

  1. Molecular Targets of the Phytocannabinoids: A Complex Picture. Morales P, Hurst DP, Reggio PH. Prog Chem Org Nat Prod 103 103-131 (2017)

Articles - 2om9 mentioned but not cited (4)

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Reviews citing this publication (14)

  1. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. O'Sullivan SE. Br J Pharmacol 152 576-582 (2007)
  2. An update on PPAR activation by cannabinoids. O'Sullivan SE. Br J Pharmacol 173 1899-1910 (2016)
  3. PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease. Corona JC, Duchen MR. Free Radic Biol Med 100 153-163 (2016)
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  5. Cannabinoids, inflammation, and fibrosis. Zurier RB, Burstein SH. FASEB J 30 3682-3689 (2016)
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  7. Cannabinoids in pain management: CB1, CB2 and non-classic receptor ligands. Davis MP. Expert Opin Investig Drugs 23 1123-1140 (2014)
  8. Role of PPAR γ in the Differentiation and Function of Neurons. Quintanilla RA, Utreras E, Cabezas-Opazo FA. PPAR Res 2014 768594 (2014)
  9. Cannabinoid receptor ligands as potential anticancer agents--high hopes for new therapies? Oesch S, Gertsch J. J Pharm Pharmacol 61 839-853 (2009)
  10. Relevance of Peroxisome Proliferator Activated Receptors in Multitarget Paradigm Associated with the Endocannabinoid System. Lago-Fernandez A, Zarzo-Arias S, Jagerovic N, Morales P. Int J Mol Sci 22 1001 (2021)
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  14. Cannabinoids and PPAR Ligands: The Future in Treatment of Polycystic Ovary Syndrome Women with Obesity and Reduced Fertility. Przybycień P, Gąsior-Perczak D, Placha W. Cells 11 2569 (2022)

Articles citing this publication (16)

  1. Time-dependent vascular actions of cannabidiol in the rat aorta. O'Sullivan SE, Sun Y, Bennett AJ, Randall MD, Kendall DA. Eur J Pharmacol 612 61-68 (2009)
  2. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists. Liberato MV, Nascimento AS, Ayers SD, Lin JZ, Cvoro A, Silveira RL, Martínez L, Souza PC, Saidemberg D, Deng T, Amato AA, Togashi M, Hsueh WA, Phillips K, Palma MS, Neves FA, Skaf MS, Webb P, Polikarpov I. PLoS One 7 e36297 (2012)
  3. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Nadal X, Del Río C, Casano S, Palomares B, Ferreiro-Vera C, Navarrete C, Sánchez-Carnerero C, Cantarero I, Bellido ML, Meyer S, Morello G, Appendino G, Muñoz E. Br J Pharmacol 174 4263-4276 (2017)
  4. Mode of peroxisome proliferator-activated receptor γ activation by luteolin. Puhl AC, Bernardes A, Silveira RL, Yuan J, Campos JL, Saidemberg DM, Palma MS, Cvoro A, Ayers SD, Webb P, Reinach PS, Skaf MS, Polikarpov I. Mol Pharmacol 81 788-799 (2012)
  5. Molecular mechanism of peroxisome proliferator-activated receptor α activation by WY14643: a new mode of ligand recognition and receptor stabilization. Bernardes A, Souza PC, Muniz JR, Ricci CG, Ayers SD, Parekh NM, Godoy AS, Trivella DB, Reinach P, Webb P, Skaf MS, Polikarpov I. J Mol Biol 425 2878-2893 (2013)
  6. Endogenous cannabinoid system regulates intestinal barrier function in vivo through cannabinoid type 1 receptor activation. Zoppi S, Madrigal JL, Pérez-Nievas BG, Marín-Jiménez I, Caso JR, Alou L, García-Bueno B, Colón A, Manzanares J, Manzanares J, Gómez-Lus ML, Menchén L, Leza JC. Am J Physiol Gastrointest Liver Physiol 302 G565-71 (2012)
  7. Ajulemic acid, a nonpsychoactive cannabinoid acid, suppresses osteoclastogenesis in mononuclear precursor cells and induces apoptosis in mature osteoclast-like cells. George KL, Saltman LH, Stein GS, Lian JB, Zurier RB. J Cell Physiol 214 714-720 (2008)
  8. Identification of a new hormone-binding site on the surface of thyroid hormone receptor. Souza PC, Puhl AC, Martínez L, Aparício R, Nascimento AS, Figueira AC, Nguyen P, Webb P, Skaf MS, Polikarpov I. Mol Endocrinol 28 534-545 (2014)
  9. Low-resolution molecular models reveal the oligomeric state of the PPAR and the conformational organization of its domains in solution. Bernardes A, Batista FA, de Oliveira Neto M, Figueira AC, Webb P, Saidemberg D, Palma MS, Polikarpov I. PLoS One 7 e31852 (2012)
  10. Acylamido analogs of endocannabinoids selectively inhibit cancer cell proliferation. Burstein S, Salmonsen R. Bioorg Med Chem 16 9644-9651 (2008)
  11. Ligand induced interaction of thyroid hormone receptor beta with its coregulators. Valadares NF, Polikarpov I, Garratt RC. J Steroid Biochem Mol Biol 112 205-212 (2008)
  12. Inhibition of voltage-gated Na⁺ channels by the synthetic cannabinoid ajulemic acid. Foadi N, Berger C, Pilawski I, Stoetzer C, Karst M, Haeseler G, Wegner F, Leffler A, Ahrens J. Anesth Analg 118 1238-1245 (2014)
  13. Structural requirement for PPARgamma binding revealed by a meta analysis of holo-crystal structures. Nascimento AS. Biochimie 92 499-506 (2010)
  14. A structural insight into the molecular recognition of a (-)-Delta9-tetrahydrocannabinol and the development of a sensitive, one-step, homogeneous immunocomplex-based assay for its detection. Niemi MH, Turunen L, Pulli T, Nevanen TK, Höyhtyä M, Söderlund H, Rouvinen J, Takkinen K. J Mol Biol 400 803-814 (2010)
  15. Differential effects of TR ligands on hormone dissociation rates: evidence for multiple ligand entry/exit pathways. Cunha Lima ST, Nguyen NH, Togashi M, Apriletti JW, Nguyen P, Polikarpov I, Scanlan TS, Baxter JD, Webb P. J Steroid Biochem Mol Biol 117 125-131 (2009)
  16. Deciphering the relational dynamics of AF-2 domain of PAN PPAR through drug repurposing and comparative simulations. Gul F, Parvaiz N, Azam SS. PLoS One 18 e0283743 (2023)


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