Treating Neurological Disorders Caused by Opioid Addiction – Targeting the µ Opioid Receptor

Yan Zhang, PhD, Professor, Department of Medicinal Chemistry, Virginia Commonwealth University, a recognized expert in the study of drug design and development to treat various types of diseases, has developed novel compounds to treat neurological disorders related to opioid addiction.

Drug use disorder is a growing global epidemic. In 2018, over 72,000 people died in the US alone from opioid overdose. The two current methods for treating opioid addiction include detoxification and maintenance therapy using opioid receptor antagonists, such as naloxone and naltrexone. While effective, naloxone and naltrexone have the potential to cause hepatotoxicity, cardiovascular and pulmonary problems at higher doses.

The analgesic function and addiction/abuse liability of many clinically available opiates are due to their interaction with the µ opioid receptor (MOR). A number of MOR selective antagonists and partial agonists have been used for the treatment of opioid abuse and addiction.

Dr. Zhang has designed and synthesized a number of highly selective and potent opioid antagonists. The first compound identified as a peripherally selective MOR antagonist, NAP. Since NAP’s discovery, generations of new compounds have been studied; NAQ, NAN, and NFP. In vitro competition assays showed that NAQ, NAN, and NFP have superior selectivity for the MOR over existing compounds. In vivo withdrawal studies showed that NAQ, NAN, and NFP produced significantly less withdrawal symptoms compared to naloxone at similar doses. The findings suggest that these compounds may serve as a lead compound to develop novel dual selective ligands for treating opioid addiction and abuse.

The technology

Pharmacology Data Summary

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  • Treatment of neurological disorders: drug abuse, drug addiction, alcoholism, neurological disorders related to opioid receptor functions
  • Fewer withdrawal symptoms than current treatment
  • Higher affinity and specificity for MOR


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Additional information


Yan Zhang, Ph.D.
Medicinal Chemistry

External resources:

  • Guo Li, Lindsey C. Aschenbach, Jianyang Chen, Michael P. Cassidy, David L. Stevens, Bichoy H. Gabra, Dana E. Selley, William L. Dewey, Richard B. Westkaemper, Yan Zhang. Design, Synthesis and Biological Evaluation of 6α- and 6β-N-Heterocyclic Substituted Naltrexamine Derivatives as Mu Opioid Receptor Selective Antagonists. J. Med. Chem. 2009, 52, 1416-27. PMID: 19199782. PMCID: PMC2880636.
  • Yunyun Yuan, Guo Li, Hengjun He, David L. Stevens, Patrick Kozak, Krista L. Scoggins, Pallabi Mitra, Phillip M. Gerk, Dana E. Selley, William L. Dewey, Yan Zhang. Identification of 6- and 6-N-Heterocyclic Substituted Naltrexamine Derivatives as Novel Leads to Development of Mu Opioid Receptor Selective Antagonists. ACS Chem. Neurosci. 2011, 2 (7), 346–351. PMCID: PMC3369747.
  • Yan Zhang, Amanda Braithwaite, Yunyun Yuan, John M. Streicher, Edward J. Bilsky. Behavioral and Cellular Pharmacology Characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) as a Mu Opioid Receptor Selective Ligand. European J. Pharmacology, 2014, 736, 124-130. PMID: 24815322. PMCID: PMC4073486.
  • Ahmad A. Altarifi, Yunyun Yuan, Yan Zhang, Dana E. Selley, S. Stevens Negus. Effects of the Novel, Selective and Low-Efficacy Mu Opioid Receptor Ligand NAQ on Intracranial Self-Stimulation in Rats. Psychopharmacology (Berl). 2015, 232, 815-24. PMID: 25178814. PMCID: PMC4310756.
  • Justin N. Siemian, Samuel Obeng, Yan Zhang, Yanan Zhang, Jun-Xu Li. Antinociceptive interactions between the imidazoline I2 receptor agonist 2-BFI and opioids in rats: role of efficacy at the mu opioid receptor. Pharm. Expt. Ther. 2016 357(3):509-19. PMID: 27056847.
  • Samuel Obeng, Yunyun Yuan, Abdulmajeed Jali, Dana E. Selley, Yan Zhang. In vitro and in vivo functional profile characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3-carboxamido)morphinan (NAQ) as a low efficacy mu opioid receptor modulator. European Journal of Pharmacology. 2018, 827, 32-40. PMID: 29530590. PMCID: PMC5890425.
  • Jeremy C. Cornelissen, Samuel Obeng, Kenner C. Rice, Yan Zhang, S. Stevens Negus, Matthew L. Banks. Application of Receptor Theory to the Design and Use of Fixed-Proportion Mu-Opioid Agonist and Antagonist Mixtures in Rhesus Monkeys. J. Pharmacol. Exp. Ther. 2018, 365(1), 37-47. PMID: 29330156. PMCID: PMC5830633.
  • Samuel Obeng, Huiqun Wang, Abdulmajeed Jali, David L. Stevens, Hamid I. Akbarali, William L. Dewey, Dana E. Selley, Yan Zhang. Structure activity relationship studies of 6β- and 6α-indolylacetamidonaltrexamine derivatives as bitopic mu opioid receptor modulators and elaboration of ‘message-address concept’ to comprehend their functional conversion. ACS Chemical Neuroscience, Allostery special issue, 2018. doi: 10.1021/acschemneuro.8b00349. [Epub ahead of print]. PMID: 30156823.

Patent status:

Selective, non-peptide antagonists for the MOR and their methods of use are protected by an extensive international patent estate. Issued patents and patent applications ensure patent protection until 2030 at a minimum with the potential for additional protection. The novel compound, NFP, is the newest formulation with the potential for 20+ years of patent coverage. The patent estate claims: formulation of compounds and close analogs and methods of use for treating conditions related to addiction in which MOR is involved. Some of the patent family portfolio includes: 8,772,308; 8,980,908; 16/301,765; 16/306,232. Additional information about the patent estate is available upon request.



VCU Tech #:

09-004F, 13-106F, 16-064F, 16-065F, 18-094F

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Magdalena K. Morgan, Ph.D.
Licensing Associate
(804) 827-6095