Identification of a dual δ OR antagonist/μ OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d)

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4869-72. doi: 10.1016/j.bmcl.2012.05.042. Epub 2012 May 24.


A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships (SARs) relative to heterocyclic core, opioid receptor (OR) agonists 4. Compound 5l was found to have very favorable OR binding affinities at the δ and μ ORs (r K(i) δ=1.3 nM; r K(i) μ=0.9 nM; h K(i) μ=1.7 nM), with less affinity for the κ OR (gp K(i) κ=55 nM). The OR functional profile for 5l varied from the previously described dual δ/μ OR agonists 4, with 5l being a potent, mixed dual δ OR antagonist/μ OR agonist [δ IC(50)=89 nM (HVD); μ EC(50)=1 nM (GPI); κ EC(50)=1.6 μM (GPC)]. Compound 5l has progressed through a clinical Phase II Proof of Concept study on 800 patients suffering from diarrhea-predominant Irritable Bowel Syndrome (IBS-d). This Phase II study was recently completed successfully, with 5l demonstrating statistically significant efficacy over placebo.

MeSH terms

  • Clinical Trials, Phase II as Topic
  • Diarrhea / etiology*
  • Humans
  • Irritable Bowel Syndrome / complications
  • Irritable Bowel Syndrome / drug therapy*
  • Molecular Structure
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, mu / agonists*
  • Structure-Activity Relationship


  • Receptors, Opioid, delta
  • Receptors, Opioid, mu