From Molecular Design to Biological Evaluation: Structure-Activity Relationship Studies of Novel Mu-Opioid Receptor Modulators

Authors

• Preet Shah, Virginia Commonwealth University

Original Publication Date

2026

Document Type

Presentation

Comments

12th Annual VCU 3MT® Competition, held on October 9, 2026.

Abstract

Opioid use disorder (OUD) imposes immense health and economic burdens, yet current pharmacotherapies remain limited. To address this, this research targets the mu-opioid receptor, the primary brain mechanism mediating opioid reward, to develop selective antagonists with reduced side effects. Building upon previous lead molecules NAP (peripherally restricted) and NIH (central activity with reduced selectivity), 26 novel NIH analogs were synthesized. This work aims to optimize central nervous system penetration while maximizing target selectivity, advancing safer candidate medications for OUD treatment and long-term recovery.

Accessibility Note

Content is digitally accessible 2026

Transcription

From the School of Pharmacy, Preet Shah: From Molecular Design to Biological Evaluation: Structure-Activity Relationship Studies of Novel Mu-Opioid Receptor Modulators. Their advisor is Dr. Yan Zhang. Can you imagine surviving an opioid overdose and asking the question, what happens next? Millions of people suffer from opioid use disorder and are vulnerable to its effects of cravings, withdrawal, and potential to reuse opioids again. There's also over 125,000 deaths every year from an opioid overdose and an economic burden that adds up to over two trillion dollars every year. This is why opioid use disorder is an important area to study. There are medications like Narcan and Opvi that reverse an opioid overdose and medications like methadone, buprenorphine and naltrexone that are good treatment options for opioid use disorder. These are some life-saving medications, but they have their limitations, and no single treatment option works for everyone. That is why my research focuses on the development of new treatment options for opioid use disorder, OUD. Our research specifically focuses on the mu-opioid receptor, which you can think of as a switch through which opioids act in the brain and produce their euphoric effects. Antagonists, on the other hand, are molecules that block this switch and prevent opioids from acting on it. The challenge is to create these molecules such that they can block this switch effectively while lowering unwanted effects. The Zhang lab has spent years working towards this goal beginning with a molecule called NAP. NAP is a molecule that is able to selectively block this mu-opioid receptor switch meaning it can pick this switch over the other switches but it acts outside the brain which limits is further of which limits is further development then the researchers changed a small part of nap to make nah nah was now a molecule that was able to act in the brain but had losses selectivity this is where my research comes in where I have designed 26 new variations of NIH to ask the question, how can we change NIH to maintain its ability to act in the brain while enhancing its selectivity? And my hope is that with this research, we can guide the future development of opioid use disorder treatment options and answer the question, anyone asking what happens next, that they have a chance at a lasting recovery. Thank you.

Rights

© The Author