# Structural Basis of Opioid Receptor Function

> **NIH NIH R37** · STANFORD UNIVERSITY · 2020 · $616,324

## Abstract

PI: Brian Kobilka
Structural Basis for Opioid Receptor Function
Abstract of Research Plan
The most powerful analgesic and addictive properties of opiate alkaloids are mediated by the µOR.
As the receptor primarily responsible for the effects of opium, the μOR is one of the oldest drug
targets within the pharmacopeia. Opioid receptors are highly versatile signaling molecules.
Activation of the μOR results in signaling through the heterotrimeric G protein Gi, resulting in
analgesia and sedation as well as euphoria and physical dependence. The μOR can also signal
through arrestin, and this pathway has been attributed to adverse effects of opioid analgesics
including tolerance, respiratory suppression, and constipation. The μOR has been the subject of
intense focus for drug-discovery efforts over the past century, with the identification of numerous
ligands of varying efficacy. These drugs occupy a wide chemical spectrum, from small organic
molecules to a variety of endogenous and synthetic peptides. Recently it has been shown that
drugs may differ in their ability to promote activation of the Gi or arrestin pathways, a property
referred to a “bias”. It has recently been shown that Gi-biased drugs such as PZM21, identified
during the initial funding period, may have better therapeutic profiles than non-biased agonists
such as morphine. The goal of research funded by this award is to provide structural insights into
biased signaling that will facilitate our ability to develop the next generation of opioid analgesics
with fewer adverse effects and less addictive potential.
Specific Aims for the next period of funding (described in more detail at the end of the Progress
Report)
Aim 1. Determine the structure of an opioid receptor in complex with Gi.
Aim 2. Determine the structure of the µOR bound to a G protein biased agonist.
Aim 3. Determine the structure of an opioid receptor in complex with arrestin.
Aim 4 . Characterize the effect of different ligands on µOR structure and dynamics.
Resource Sharing Plan:
We will share all materials generated during the course of our studies. These will be distributed freely before
or immediately after publication, and we will provide relevant protocols and published data upon request.
Material transfers will be made with no more restrictive terms than in the Simple Letter Agreement (SLA) or
the Uniform Biological Materials Transfer Agreement (UBMTA) and without reach through requirements.
We will adhere to the NIH Grant Policy on Sharing of Unique Research Resources including the Sharing of
Biomedical Research Resources Principles and Guidelines for Recipients of NIH Grants and Contracts
issued in December, 1999 (http://www.ott.nih.gov/policy/rt_guide_final.htmlȌ. Should any intellectual
property arise which requires a patent, we will ensure that the technology (materials and data) remains
widely available to the research community in accordance with the NIH Principles and Guidelines document.
In addition, crystall...

## Key facts

- **NIH application ID:** 9931188
- **Project number:** 5R37DA036246-08
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Brian K Kobilka
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $616,324
- **Award type:** 5
- **Project period:** 2013-06-15 → 2022-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931188

## Citation

> US National Institutes of Health, RePORTER application 9931188, Structural Basis of Opioid Receptor Function (5R37DA036246-08). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9931188. Licensed CC0.

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