Identification of a highly potent and selective CB2 agonist, RQ-00202730, for the treatment of irritable bowel syndrome

Bioorg Med Chem Lett. 2015 Jan 15;25(2):236-40. doi: 10.1016/j.bmcl.2014.11.062. Epub 2014 Dec 3.

Abstract

Herein we report the identification of a highly potent and selective CB2 agonist, RQ-00202730 (40), obtained by lead optimization of the benzimidazole scaffold. Compound 40 showed strong agonistic activity with an EC50 of 19nM and excellent selectivity (>1300-fold) over the CB1 receptor. Compound 40 displayed a dose dependent analgesic effect on TNBS-induced visceral hypersensitivity in rats by oral administration (ED50 0.66mg/kg at 2.5h after oral administration). In addition, 40 did not show a significant effect on body temperature in rats after oral administration at 300mg/kg. These findings suggest that highly selective CB2 agonists will be effective agents for IBS therapy.

Keywords: Benzimidazole; CB2 agonist; Cannabinoid receptor; Irritable bowel syndrome.

MeSH terms

  • Administration, Oral
  • Animals
  • Cannabinoid Receptor Agonists / administration & dosage*
  • Cannabinoid Receptor Agonists / chemistry*
  • Cannabinoid Receptor Agonists / metabolism
  • Dose-Response Relationship, Drug
  • Irritable Bowel Syndrome / drug therapy*
  • Irritable Bowel Syndrome / metabolism
  • Male
  • Rats
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / metabolism
  • Treatment Outcome

Substances

  • Cannabinoid Receptor Agonists
  • Receptor, Cannabinoid, CB2