Mu Opioid Receptor Agonists with Dopamine D3 Receptor Antagonism: Toward Developing Analgesics with Less Abuse Potential

Abstract

Opioid analgesics such as morphine are widely used in clinical practice for the management of moderate to severe pain. While they are the gold standard for painkillers, they are also highly addictive: approximately 10% of patients prescribed opioids for pain‐relief develop an opioid‐use disorder. Abuse of prescription opioids and heroin has become an epidemic in the United States with opioid overdose deaths quadrupling since 1999. Opioids induce their physiological effects through the activation of the mu opioid receptor (MOR). Interestingly, co‐administration of dopamine D3 (DRD3) receptor antagonists with opioids attenuates the self‐administration and rewarding effects of the drugs, but has no effect on their ability to relieve pain. This suggests that the development of compounds that both activate MOR and antagonize DRD3 may be a means to maintain the beneficial effects of opioids, while reducing their abuse potential. We have recently developed a library of small molecules with a novel scaffold that are agonists at MOR. Herein we screened our MOR agonists for antagonism at DRD3 in a DRD3/βarrestin enzyme fragment complementation assay. We identified multiple compounds that antagonize DRD3 that are as potent as Sulpiride, a known DRD3 antagonist. Further characterization of these MOR agonists with polypharmacology at DRD3 may allow for the development of opioid analgesics with reduced abuse liabilities.Support or Funding InformationFunded by NIDA grant R01 DA033073 to LMB Fellowship to NMS: NSF award 1359369. and TDB, and NSF Undergraduate ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.