R42DA056254
Project Grant
Overview
Grant Description
Development of negative allosteric modulators of the mu-opioid receptor for the management of opioid use disorder - Abstract
There is a significant need for new treatments to manage the multitude of patients suffering from opioid use disorder (OUD).
Buprenorphine and methadone are both effective medications for OUD but are agonists with potential for abuse and diversion, and with methadone the risk of respiratory depression and overdose death.
Moreover, these compounds are not effective in relapse situations.
The antagonist naltrexone is an alternative that does prevent relapse but has poor patient compliance due to its complete blockade of the mu-opioid system.
We have discovered compounds that act as non-competitive antagonists of the mu-opioid receptor (MOR).
These compounds interact with a novel site on the receptor to function as allosteric antagonists, also called NAMS or negative allosteric modulators.
They reduce the activity of MOR agonists in a fashion that is non-surmountable and that does not completely shut down the receptor, thereby providing the ability to reduce opioid actions in individuals with OUD, potentially without inducing withdrawal and lacking the negative side-effects of current agonist or antagonist treatments.
Our hypothesis is that NAMS of MOR (MOR-NAMS) could be developed as effective non-agonist treatments for OUD by targeting MOR in a novel way leading to our goal of identifying proprietary MOR-NAMS as an improved, non-agonist treatment for OUD.
In Phase 1 of this STTR application (R41, DA056254) we identified several proprietary MOR-NAM’s with high potency at MOR, that are active in vitro, block actions of morphine in mice and are orally bioavailable.
The objective of the Phase 2 application is to develop these NAM molecules into druggable compounds with favorable DMPK characteristics, no obvious toxicity or off-target liabilities, a complete lack of any MOR agonist activity and that inhibit fentanyl seeking behavior in rat self-administration models.
At the end of this Phase 2 work, we expect to be in a very favorable position to seek strategic partnerships to fund large-scale chemical synthesis and in vivo toxicology as we move towards an IND application and eventual clinical trials.
There is a significant need for new treatments to manage the multitude of patients suffering from opioid use disorder (OUD).
Buprenorphine and methadone are both effective medications for OUD but are agonists with potential for abuse and diversion, and with methadone the risk of respiratory depression and overdose death.
Moreover, these compounds are not effective in relapse situations.
The antagonist naltrexone is an alternative that does prevent relapse but has poor patient compliance due to its complete blockade of the mu-opioid system.
We have discovered compounds that act as non-competitive antagonists of the mu-opioid receptor (MOR).
These compounds interact with a novel site on the receptor to function as allosteric antagonists, also called NAMS or negative allosteric modulators.
They reduce the activity of MOR agonists in a fashion that is non-surmountable and that does not completely shut down the receptor, thereby providing the ability to reduce opioid actions in individuals with OUD, potentially without inducing withdrawal and lacking the negative side-effects of current agonist or antagonist treatments.
Our hypothesis is that NAMS of MOR (MOR-NAMS) could be developed as effective non-agonist treatments for OUD by targeting MOR in a novel way leading to our goal of identifying proprietary MOR-NAMS as an improved, non-agonist treatment for OUD.
In Phase 1 of this STTR application (R41, DA056254) we identified several proprietary MOR-NAM’s with high potency at MOR, that are active in vitro, block actions of morphine in mice and are orally bioavailable.
The objective of the Phase 2 application is to develop these NAM molecules into druggable compounds with favorable DMPK characteristics, no obvious toxicity or off-target liabilities, a complete lack of any MOR agonist activity and that inhibit fentanyl seeking behavior in rat self-administration models.
At the end of this Phase 2 work, we expect to be in a very favorable position to seek strategic partnerships to fund large-scale chemical synthesis and in vivo toxicology as we move towards an IND application and eventual clinical trials.
Awardee
Funding Goals
TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Ann Arbor,
Michigan
481091276
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 92% from $1,567,215 to $3,012,228.
Eleven Therapeutics was awarded
Novel MOR-NAMS for Opioid Use Disorder Management
Project Grant R42DA056254
worth $3,012,228
from National Institute on Drug Abuse in August 2022 with work to be completed primarily in Ann Arbor Michigan United States.
The grant
has a duration of 4 years and
was awarded through assistance program 93.279 Drug Abuse and Addiction Research Programs.
The Project Grant was awarded through grant opportunity PHS 2023-2 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42] Clinical Trial Not Allowed).
SBIR Details
Research Type
STTR Phase II
Title
Development of negative allosteric modulators of the mu-opioid receptor for the management of opioid use disorder
Abstract
Abstract There is a significant need for new treatments to manage the multitude of patients suffering from opioid use disorder (OUD). Buprenorphine and methadone are both effective medications for OUD but are agonists with potential for abuse and diversion, and with methadone the risk of respiratory depression and overdose death. Moreover, these compounds are not effective in relapse situations. The antagonist naltrexone is an alternative that does prevent relapse but has poor patient compliance due to its complete blockade of the mu-opioid system. We have discovered compounds that act as non-competitive antagonists of the mu-opioid receptor (MOR). These compounds interact with a novel site on the receptor to function as allosteric antagonists, also called NAMs or Negative Allosteric Modulators. They reduce the activity of MOR agonists in a fashion that is non-surmountable and that does not completely shut down the receptor, thereby providing the ability to reduce opioid actions in individuals with OUD, potentially without inducing withdrawal and lacking the negative side-effects of current agonist or antagonist treatments. Our hypothesis is that NAMs of MOR (MOR-NAMs) could be developed as effective non- agonist treatments for OUD by targeting MOR in a novel way leading to our goal of identifying proprietary MOR-NAMs as an improved, non-agonist treatment for OUD. In Phase 1 of this STTR application (R41, DA056254) we identified several proprietary MOR-NAM’s with high potency at MOR, that are active in vitro, block actions of morphine in mice and are orally bioavailable. The objective of the Phase 2 application is to develop these NAM molecules into druggable compounds with favorable DMPK characteristics, no obvious toxicity or off-target liabilities, a complete lack of any MOR agonist activity and that inhibit fentanyl seeking behavior in rat self-administration models. At the end of this Phase 2 work, we expect to be in a very favorable position to seek strategic partnerships to fund large-scale chemical synthesis and in vivo toxicology as we towards an IND application and eventual clinical trials.
Topic Code
NIDA
Solicitation Number
PA23-232
Status
(Ongoing)
Last Modified 9/24/25
Period of Performance
8/1/22
Start Date
8/31/26
End Date
Funding Split
$3.0M
Federal Obligation
$0.0
Non-Federal Obligation
$3.0M
Total Obligated
Activity Timeline
Transaction History
Modifications to R42DA056254
Additional Detail
Award ID FAIN
R42DA056254
SAI Number
R42DA056254-499434500
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Small Business
Awarding Office
75N600 NIH National Insitute on Drug Abuse
Funding Office
75N600 NIH National Insitute on Drug Abuse
Awardee UEI
E1W7Z1DEAH23
Awardee CAGE
86HE4
Performance District
MI-06
Senators
Debbie Stabenow
Gary Peters
Gary Peters
Modified: 9/24/25