2. Academic Validation
  3. Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones

Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones

  • Bioorg Med Chem Lett. 2016 Apr 1;26(7):1827-1830. doi: 10.1016/j.bmcl.2016.02.030.
Maria Elena Meza-Aviña # 1,  Mary A Lingerfelt # 1,  Linda M Console-Bram 2,  Thomas F Gamage 2,  Haleli Sharir 2,  Kristen E Gettys 1,  Dow P Hurst 1,  Evangelia Kotsikorou 3,  Derek M Shore 1,  Marc G Caron 4,  Narasinga Rao 1,  Larry S Barak 4,  Mary E Abood 2,  Patricia H Reggio 1,  Mitchell P Croatt 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Natural Products and Drug Discovery Center, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United States.
  • 2 Center for Substance Abuse Research, Temple University, Philadelphia, Pennsylvania 19140, United States.
  • 3 Department of Chemistry, University of Texas - Pan American, Edinburg, Texas 78539, United States.
  • 4 Duke University Medical Center, Durham, North Carolina 27709, United States.
  • # Contributed equally.
PMID: 26916440 DOI: 10.1016/j.bmcl.2016.02.030
Abstract

A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly accessed to explore initial structure-activity relationships. The design of analogues was guided by the docking of potential compounds into a model of the inactive form of GPR55. The results of the assays were used to learn more about the binding pocket of GPR55. With this oxadiazolone scaffold, it was determined that modification of the aryl group adjacent to the oxadiazolone ring was often detrimental and that the distal cyclopropane was beneficial for activity. These results will guide further exploration of this receptor.

Keywords

Antagonist; Cancer; GPCR; GPR55; Neuropathic pain.

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