Opioids such as morphine are the most potent and efficacious agents currently available for the treatment of moderate to severe acute and chronic pain. These drugs primarily act through the mu subtype of the opioid receptors. However, their therapeutic use is limited due to respiratory depression, opioid-induced bowel dysfunction, development of tolerance and dependence, and renewed concerns around addiction liabilities. There is an urgent unmet medical need for the discovery and development of novel analgesics that are as efficacious as morphine but devoid of significant side effects. Delta receptor gene knockout/knockdown experiments and studies using selective antagonists and bifunctional (mu agonist/delta antagonist) compounds have provided evidence that activation of mu receptor function with simultaneous suppression of delta receptor function produces analgesic effects with greatly diminished mu receptor mediated side effects. Thus, compounds possessing dual but opposing functional activity of mu receptor agonism and delta receptor antagonism have the potential to exhibit broad-spectrum analgesia with a wide safety margin and therapeutic index. Therefore, we have been pursuing the discovery of small molecules possessing the dual functional profile of mu agonism/delta antagonism. To this end, we recently discovered compounds possessing a balanced profile of high-affinity binding at mu and delta receptors and possessing mixed mu agonist/delta antagonist functional activity. In addition these compounds had a diminished propensity to produce tolerance, dependence and abuse liability. In this proposed project, our goal is to develop novel orally active mu agonist/delta antagonist compounds. The approach builds upon the structure-activity relationships determined for the lead series. The medicinal chemistry lead optimization strategy includes rational drug design utilizing crystal structure information on mu and delta receptors that became recently available as well as multi- parametric lead optimization for the improvement of physicochemical and pharmacokinetic properties. To achieve the goal of identifying lead preclinical candidates we will (1) design and synthesize new compounds based upon activity and in vitro pharmacokinetic properties (2) perform in vitro screening to determine opioid receptor binding and functional activity (3) determine the in vitro and in vivo pharmacokinetic profile (bioavailability, half-lifeand CNS levels) to select compounds for (4) comprehensive in vivo analgesic efficacy and side effect profiling in rodents. These goals will be accomplished through a collaborative effort involving a team with extensive experience in drug design, medicinal chemistry, computational chemistry, opioid biochemistry and molecular biology, pharmacokinetics, opioid pharmacology, and drug development.

Public Health Relevance

Current treatment options for alleviating severe acute and chronic pain using powerful opioid analgesics such as morphine suffer from limitations caused by their side effects such as respiratory depression, constipation, and the development of tolerance, dependence, and addiction liabilities. Recent research has revealed that compounds that interact with mu opioid receptors as agonists and with delta opioid receptors as antagonists could emerge as powerful analgesics with a diminished propensity to produce such side effects. The proposed effort focusing on discovery of orally active compounds possessing mixed mu agonist/delta antagonist activity could potentially lead to the development of novel, improved analgesic drugs for the treatment of patients suffering from chronic pain.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Drug Discovery for the Nervous System Study Section (DDNS)
Program Officer
Hillery, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Southern Research Institute
United States
Zip Code