Switching cannabinoid response from CB(2) agonists to FAAH inhibitors

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1322-6. doi: 10.1016/j.bmcl.2014.01.056. Epub 2014 Jan 28.

Abstract

A series of 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated as FAAH inhibitors. The pharmacological results led to identify structure-activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that compounds 10 and 11 inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.

Keywords: CB(2); Cannabinoid; FAAH; IBD; Isoxazoles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / chemistry
  • Adamantane / pharmacology
  • Adamantane / therapeutic use
  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / metabolism
  • Animals
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Body Weight / drug effects
  • Cannabinoids / chemistry*
  • Cannabinoids / pharmacology
  • Cannabinoids / therapeutic use
  • Colitis / drug therapy
  • Colitis / pathology
  • Disease Models, Animal
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacology
  • Isoxazoles / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein Binding
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Cannabinoids
  • Enzyme Inhibitors
  • Isoxazoles
  • Receptor, Cannabinoid, CB2
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • Adamantane