Potential compounds for prevention and treatment of prescription opioid abuse

2017

Challenge

The dramatic increase in use of prescription opioid analgesics, such as oxycodone, parallels escalated opioid dependence and drug-related deaths worldwide. Despite decades of research, a non-addictive opioid analgesic has yet to advance to the clinic. Compelling preclinical evidence suggests a crucial involvement of brain dopamine D3 receptors (D3R) in drug reward and addiction, providing a potential target for reducing opioid abuse liability without diminishing pain relief.

Advance

IRP researchers led by Amy Newman, Ph.D., used a structure-based approach to discover highly D3R-selective antagonist/partial agonist compounds that, in animal models, reduce oxycodone self-administration, naloxone precipitated withdrawal, and reinstatement of drug seeking behaviors, without affecting analgesia.

Impact

The team’s data suggest that selective D3R blockade may reduce the development of opioid dependence without diminishing the effectiveness of prescription pain killers. In addition, the lead molecules identified may offer a potential stand-alone or adjunctive treatment to existing medications for the treatment of opioid use disorders. Recent licensing of this NIH technology by pharmaceutical industry partners has initiated further development of these promising molecules to combat the opioid epidemic through prevention and treatment.

Publications

Kumar V, Bonifazi A, Ellenberger MP, Keck TM, Pommier E, Rais R, Slusher BS, Gardner E, You ZB, Xi ZX, Newman AH. (2016). Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence TreatmentJ Med Chem. 59(16):7634-50