Endocannabinoid Analogs as Anti-inflammatory Agents

Summary

Principal Investigator: SUMNER HOWARD BURSTEIN
Abstract: The endocannabinoid anandamide (arachidonyl ethanolamide) is the principal member of a family of regulators that are involved in modulating a number of biological actions including analgesia and specific aspects of the inflammatory response. It has been suggested that acid congeners of anandamide could exist as endogenous substances. This hypothesis was realized in a study that showed that such a substance, N-arachidonylglycine (NAGly), is indeed an endogenous constituent of many tissues and occurs at levels higher than anandamide. An interesting property of NAGly is its potent inhibitory effect on FAAH, the enzyme primarily responsible for the termination of anandamide action. FAAH is a serine hydrolase whose crystal structure was recently published, thus, opening the way for the rational study of the structural features of NAGly that confer its inhibitory properties. It has been reported that NAGly treatment in both in vitro and in vivo models, leads to a robust increase in anandamide concentrations. We therefore hypothesize that this inhibitory action is the basis for the anti-inflammatory action of NAGly and possibly other actions, e.g. analgesia. A major goal of this project is to synthesize a series of NAGly analogs as probes; these will be based on computer assisted docking analysis using the crystal structure of FAAH. The analogs will be tested in vitro as inhibitors of FAAH and compared with their effects on mediators of inflammation. The structure-activity data that will emerge from these studies will either support or refute the hypothesis. Anandamide appears to be involved in a wide range of regulatory functions through out the animal kingdom. Some examples are: the control of sensorimotor and motivational aspects of behavior, the regulation of implantation, hypotensive and bradycardic effects, cognition and drug dependence, the control of human pregnancy, sleep- wakefulness cycle, memory formation, locomotor activity, pain perception and modulation of the immune response. Thus, agents such as NAGly that can regulate in vivo anandamide levels could be effective modulators of many of these health related processes.
Funding Period: 2004-09-30 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. pmc Potential anti-inflammatory actions of the elmiric (lipoamino) acids
    Sumner H Burstein
    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
    Bioorg Med Chem 15:3345-55. 2007
  2. pmc The elmiric acids: biologically active anandamide analogs
    Sumner Burstein
    Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School Worcester, MA 01605, USA
    Neuropharmacology 55:1259-64. 2008
  3. ncbi Acylamido analogs of endocannabinoids selectively inhibit cancer cell proliferation
    Sumner Burstein
    Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, MA 01605, USA
    Bioorg Med Chem 16:9644-51. 2008
  4. pmc Cannabinoids, endocannabinoids, and related analogs in inflammation
    Sumner H Burstein
    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, Massachusetts 01605, USA
    AAPS J 11:109-19. 2009
  5. pmc Identification of endogenous acyl amino acids based on a targeted lipidomics approach
    Bo Tan
    Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University Bloomington IN 47405, USA
    J Lipid Res 51:112-9. 2010
  6. ncbi The cannabinoid acids, analogs and endogenous counterparts
    Sumner H Burstein
    Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, MA 01605, USA Electronic address
    Bioorg Med Chem 22:2830-43. 2014

Detail Information

Publications6

  1. pmc Potential anti-inflammatory actions of the elmiric (lipoamino) acids
    Sumner H Burstein
    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
    Bioorg Med Chem 15:3345-55. 2007
    ..The ear edema assay results were generally in agreement with the prostaglandin assay findings indicating a connection between them...
  2. pmc The elmiric acids: biologically active anandamide analogs
    Sumner Burstein
    Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School Worcester, MA 01605, USA
    Neuropharmacology 55:1259-64. 2008
    ..Future studies should be aimed at elucidating the actions of all of the members of this interesting family of molecules...
  3. ncbi Acylamido analogs of endocannabinoids selectively inhibit cancer cell proliferation
    Sumner Burstein
    Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, MA 01605, USA
    Bioorg Med Chem 16:9644-51. 2008
    ..No clear structure-activity pattern could be derived from these studies since the intensity of the inhibitory action seemed to depend on three factors, namely, the fatty acid, the amine group and the cell type...
  4. pmc Cannabinoids, endocannabinoids, and related analogs in inflammation
    Sumner H Burstein
    Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, Massachusetts 01605, USA
    AAPS J 11:109-19. 2009
    ..This differentiates these cannabinoids from cyclooxygenase-2 inhibitors that suppress the synthesis of eicosanoids that promote the induction of the inflammatory process...
  5. pmc Identification of endogenous acyl amino acids based on a targeted lipidomics approach
    Bo Tan
    Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, Indiana University Bloomington IN 47405, USA
    J Lipid Res 51:112-9. 2010
    ..We successfully identified 50 novel endogenous acyl amino acids present at 0.2 to 69 pmol g(-1) wet rat brain...
  6. ncbi The cannabinoid acids, analogs and endogenous counterparts
    Sumner H Burstein
    Department of Biochemistry and Molecular Pharmacology, The University of Massachusetts Medical School, Worcester, MA 01605, USA Electronic address
    Bioorg Med Chem 22:2830-43. 2014
    ..Also presented are reports on analogs of the acids that provide opportunities for the development of novel therapeutic agents, such as ajulemic acid. ..