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

作者：Meza Avina Maria Elena; Lingerfelt Mary A; Console Bram Linda M; Gamage Thomas F; Sharir Haleli; Gettys Kristen E; Hurst Dow P; Kotsikorou Evangelia; Shore Derek M; Caron Marc G; Rao Narasinga; Barak Larry S; Abood Mary E^*; Reggio Patricia H^*; Croatt Mitchell P^*

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(7): 1827-1830.

DOI：10.1016/j.bmcl.2016.02.030

• GPR55
• Neuropathic pain
• GPCR
• Antagonist
• Cancer

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.

• 出版日期2016-4-1