UG3NS141745
Cooperative Agreement
Overview
Grant Description
Neurotensin 1 allosteric modulator for the treatment of pain - project summary
The NIH HEAL Initiative aims to tackle two ongoing health care crises: opioid use disorder and uncontrolled pain.
Pharmacological approaches targeting both crises are urgently needed.
The neurotensin receptor 1 (NTR1) has been a sought-after target for the treatment of both pain and addiction, but development of balanced NTR1 agonists is precluded by their severe side effects.
As a G protein-coupled receptor (GPCR), NTR1 signals through the activation of G proteins and β-arrestins (e.g., ARRB2).
ARRB2 attenuates drug reward and suppresses pain via regulation of both GPCRs and non-GPCRs, including the NMDA receptor.
We have demonstrated in rodents that SBI-553, a novel ARRB2-biased allosteric modulator (BAM) of NTR1, attenuates opioid reward and the reinforcing effects of psychostimulants without the side effects characteristic of balanced NTR1 signaling.
Cryo-EM studies demonstrate that SBI-553 binds at an intracellular allosteric site and acts like a molecular glue, directing signaling to ARRB2 in the presence or absence of agonists.
Recently we have shown that NTR1 BAMs produce potent antinociception in rodent models, a finding that builds off previous reports that neurotensin, NTR1’s endogenous ligand, provided more potent pain relief than morphine through a mechanism that is independent of opioid receptors.
NTR1 BAMs raise nociceptive thresholds in wild-type mice, but not in NTSR1−/− or ARRB2−/− (knockout) mice, confirming the mechanistic requirement for NTR1 and ARRB2.
Local or systemic delivery of NTR1 BAMs reduced hypersensitivity in mouse models of postoperative and neuropathic pain and suppressed excitatory synaptic transmission and NMDAR/ERK signaling in spinal cord nociceptive neurons.
Additionally, NTR1 BAMs suppressed C-fiber-induced responses in vivo and action potential firing in mouse and human nociceptive sensory neurons in vitro.
Collectively, our findings indicate that NTR1 BAMs are an exciting and novel approach to develop a first-in-class non-opioid drug for the treatment of pain.
In this application, we outline our plan to optimize and develop such a drug for postoperative pain.
In the UG3 stage, we will leverage the structure activity relationships developed around SBI-553 and, through a structure-based design lead optimization process, refine and improve the properties of the leads.
Co-structures of leads with NTR1 will be determined through cryo-EM, such that the iterative medicinal chemistry, design-make-test cycle is informed by computational predictions using both artificial intelligence and structure-based drug design.
In the UH3 phase, the objective is to derive advanced leads with excellent in vivo potency in acute inflammatory pain, surgical pain, and chronic neuropathic pain models, outstanding drug-like properties, and no limiting CV or CNS safety risk.
In the UH3 phase, the selected clinical candidate will be subjected to a standard battery of required IND-enabling studies, leading to an investigational new drug application (IND).
Upon acceptance of the IND, we will conduct a Phase I, single ascending dose study in healthy volunteers to assess the safety, tolerability, and PK of our clinical candidate.
The NIH HEAL Initiative aims to tackle two ongoing health care crises: opioid use disorder and uncontrolled pain.
Pharmacological approaches targeting both crises are urgently needed.
The neurotensin receptor 1 (NTR1) has been a sought-after target for the treatment of both pain and addiction, but development of balanced NTR1 agonists is precluded by their severe side effects.
As a G protein-coupled receptor (GPCR), NTR1 signals through the activation of G proteins and β-arrestins (e.g., ARRB2).
ARRB2 attenuates drug reward and suppresses pain via regulation of both GPCRs and non-GPCRs, including the NMDA receptor.
We have demonstrated in rodents that SBI-553, a novel ARRB2-biased allosteric modulator (BAM) of NTR1, attenuates opioid reward and the reinforcing effects of psychostimulants without the side effects characteristic of balanced NTR1 signaling.
Cryo-EM studies demonstrate that SBI-553 binds at an intracellular allosteric site and acts like a molecular glue, directing signaling to ARRB2 in the presence or absence of agonists.
Recently we have shown that NTR1 BAMs produce potent antinociception in rodent models, a finding that builds off previous reports that neurotensin, NTR1’s endogenous ligand, provided more potent pain relief than morphine through a mechanism that is independent of opioid receptors.
NTR1 BAMs raise nociceptive thresholds in wild-type mice, but not in NTSR1−/− or ARRB2−/− (knockout) mice, confirming the mechanistic requirement for NTR1 and ARRB2.
Local or systemic delivery of NTR1 BAMs reduced hypersensitivity in mouse models of postoperative and neuropathic pain and suppressed excitatory synaptic transmission and NMDAR/ERK signaling in spinal cord nociceptive neurons.
Additionally, NTR1 BAMs suppressed C-fiber-induced responses in vivo and action potential firing in mouse and human nociceptive sensory neurons in vitro.
Collectively, our findings indicate that NTR1 BAMs are an exciting and novel approach to develop a first-in-class non-opioid drug for the treatment of pain.
In this application, we outline our plan to optimize and develop such a drug for postoperative pain.
In the UG3 stage, we will leverage the structure activity relationships developed around SBI-553 and, through a structure-based design lead optimization process, refine and improve the properties of the leads.
Co-structures of leads with NTR1 will be determined through cryo-EM, such that the iterative medicinal chemistry, design-make-test cycle is informed by computational predictions using both artificial intelligence and structure-based drug design.
In the UH3 phase, the objective is to derive advanced leads with excellent in vivo potency in acute inflammatory pain, surgical pain, and chronic neuropathic pain models, outstanding drug-like properties, and no limiting CV or CNS safety risk.
In the UH3 phase, the selected clinical candidate will be subjected to a standard battery of required IND-enabling studies, leading to an investigational new drug application (IND).
Upon acceptance of the IND, we will conduct a Phase I, single ascending dose study in healthy volunteers to assess the safety, tolerability, and PK of our clinical candidate.
Funding Goals
TO SUPPORT BASIC, CLINICAL, TRANSLATIONAL, AND IMPLEMENTATION RESEARCH IN THE FIELD OF SUBSTANCE USE. TO DEVELOP NEW KNOWLEDGE AND APPROACHES FOR THE PREVENTION, DIAGNOSIS, AND TREATMENT OF DRUG USE, MISUSE, AND ADDICTION, DRUG OVERDOSE, AND RELATED HEALTH OUTCOME, 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 SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) LEGISTLATION IS INTENDED TO 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; 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
La Jolla,
California
920371005
United States
Geographic Scope
Single Zip Code
Sanford Burnham Prebys Medical Discovery Institute was awarded
NTR1 BAMs for Pain Treatment Development
Cooperative Agreement UG3NS141745
worth $3,855,681
from the National Institute of Neurological Disorders and Stroke in April 2026 with work to be completed primarily in La Jolla California United States.
The grant
has a duration of 2 years and
was awarded through assistance program 93.279 Drug Abuse and Addiction Research Programs.
The Cooperative Agreement was awarded through grant opportunity HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional).
Status
(Ongoing)
Last Modified 4/20/26
Period of Performance
4/15/26
Start Date
3/31/28
End Date
Funding Split
$3.9M
Federal Obligation
$0.0
Non-Federal Obligation
$3.9M
Total Obligated
Activity Timeline
Additional Detail
Award ID FAIN
UG3NS141745
SAI Number
UG3NS141745-1254039066
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Nonprofit With 501(c)(3) IRS Status (Other Than An Institution Of Higher Education)
Awarding Office
75NQ00 NIH National Institute of Neurological Disorders and Stroke
Funding Office
75NQ00 NIH National Institute of Neurological Disorders and Stroke
Awardee UEI
PHMKYKKJLQS1
Awardee CAGE
1KBK8
Performance District
CA-50
Senators
Dianne Feinstein
Alejandro Padilla
Alejandro Padilla
Modified: 4/20/26