A groundbreaking $3.9 million grant from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health (NIH), has been awarded to a consortium spearheaded by Sanford Burnham Prebys Medical Discovery Institute. This pivotal funding aims to propel the development of a novel non-opioid therapeutic for pain management, advancing it toward a Phase 1 clinical trial. The research initiative is helmed by Steven H. Olson, PhD, the executive director of medicinal chemistry at Sanford Burnham Prebys. Collaborative efforts unify expertise from Duke University and the University of Minnesota, with pivotal roles filled by Ru-Rong Ji, PhD, and Lauren M. Slosky, PhD respectively. This award emerges from the NIH’s Helping to End Addiction Long-term (HEAL) Initiative, which is devoted to addressing the urgent public health threat posed by opioid addiction through novel approaches to pain and addiction treatment.
At the core of this initiative lies the lead compound, SBI-810, a second-generation drug candidate derived from meticulous medicinal chemistry optimization, reinforced by receptor signaling analyses and efficacy testing. These efforts leverage state-of-the-art cryo-electron microscopy structural insights alongside artificial intelligence algorithms, creating a feedback loop of molecular refinement intended to maximize therapeutic efficacy while enhancing safety profiles. This iterative approach exemplifies a sophisticated leap forward in drug design, promising a new class of pain therapeutics that avoid the pitfalls of addiction and severe side effects characteristic of opioid analgesics.
The pressing need for such innovation arises from staggering clinical statistics: each year, nearly 80% of 19 million Americans undergoing major surgeries endure postoperative pain, while over 25 million individuals suffer chronic pain worldwide. Despite the prevalence, current analgesic regimens are often insufficient or fraught with complications, notably opioid-based treatments which carry profound risks such as dependence, overdose, and myriad side effects. SBI-810 targets this unmet medical need by engaging neurotensin receptor 1 (NTR1), a G protein-coupled receptor implicated in pain signaling pathways, yet does so via an unprecedented molecular mechanism.
Unlike traditional receptor agonists that bind centrally to active sites, SBI-810 acts as a biased allosteric modulator (BAM) by attaching to a cryptic intracellular pocket within NTR1. This mode of binding selectively promotes β-arrestin-2 pathway activation while suppressing G-protein mediated signaling linked to pain propagation and deleterious physiological responses. The selective modulation offers potent analgesia without inducing hypotension or hypothermia, adverse effects that historically limited the clinical advancement of NTR1-targeting compounds. This molecular precision heralds a paradigm shift in receptor pharmacology, focusing on signal bias to uncouple therapeutic effects from side effects.
The foundational science underpinning SBI-810 builds on seminal work revealing the potent analgesic properties of neurotensin, the natural ligand for NTR1. Decades ago, neurotensin was found to surpass morphine in antinociceptive potency; however, its clinical utility was hindered by systemic side effects. Dr. Ru-Rong Ji articulates this challenge: harnessing neurotensin’s analgesic power safely required novel strategies. Using structural biology and drug design, the research team has designed compounds that selectively funnel receptor signaling into beneficial routes, overcoming this historical barrier.
Recent high-impact publications underpin the grant’s rationale. A 2025 study in Cell unveiled the multifaceted efficacy of SBI-810 across diverse rodent pain models, including postoperative, inflammatory, and neuropathic conditions. Notably, the compound modulated pain signaling in human sensory neurons, an essential translational milestone. Crucially, SBI-810 reduced opioid-induced side effects, which may enable combination therapies that enhance analgesia while mitigating opioid-related harm. Complementing this, another 2025 Nature publication elucidated the molecular architecture governing biased signaling by the parent molecule SBI-553, revealing how intracellular binding pockets redirect receptor-protein interactions. These insights lay the structural groundwork for precision drug design within the largest receptor family: G protein-coupled receptors (GPCRs).
GPCRs constitute the most extensive and versatile family of membrane receptors, orchestrating cellular responses to extracellular signals such as neurotransmitters, hormones, and environmental stimuli. Their ubiquitous role in physiology renders GPCRs prime pharmacological targets, with approximately one-third of all marketed drugs acting on these receptors. This new class of biased allosteric modulators introduces a transformative approach to modulating GPCR function, emphasizing specificity in downstream signaling cascades rather than wholesale receptor activation.
Dr. Lauren M. Slosky emphasizes the transformative potential of integrating detailed structural understanding with computational methodologies. This fusion facilitates rational drug design by predicting how structural changes in compounds translate to altered receptor behavior and clinical outcomes. Such an approach mitigates the inefficiencies and uncertainties inherent in traditional empirical drug discovery, increasing the probability of clinical success.
The grant’s structure is designed to expedite the transition from laboratory discovery to clinical application through a phased strategy. The initial two-year phase concentrates on refining lead molecules by optimizing efficacy and eliminating cardiac safety liabilities detected in preliminary evaluations. Preclinical validation will employ well-established rodent pain models, with careful incorporation of sex as a biological variable to ensure broad therapeutic applicability. Subsequent phases hinge on success milestones, culminating in Investigational New Drug (IND) applications and phase 1 human safety and pharmacokinetic trials.
Underlying this endeavor is a multidisciplinary consortium that synergizes medicinal chemistry, GPCR structural biology, neurobiology, and translational pharmacology. Besides Olson, Ji, and Slosky, the team includes notable scientists such as Lawrence S. Barak, PhD, William C. Wetsel, PhD, Changlu Liu, PhD, and Michael R. Jackson, PhD. This collaborative framework exemplifies the NIH HEAL Initiative’s mission to harness interdisciplinary expertise to combat opioid addiction and chronic pain through innovative therapeutics.
Steven H. Olson reflects on the broader implications of this work, highlighting the grant’s enabling role in transforming a promising preclinical molecule into a potential new medicine. The integration of chemistry, structural biology, and rigorous in vivo pharmacology across multiple institutions provides a robust platform to tackle one of medicine’s most daunting challenges: effective, non-addictive pain relief. This initiative not only aims to alleviate suffering for millions worldwide but also to set a blueprint for future GPCR-targeted drug discovery efforts.
The NIH HEAL Initiative, which funds this research, launched in 2018 with the goal of accelerating solutions to the opioid crisis, spanning prevention, treatment of addiction, and improved pain management strategies. By fostering bold, collaborative science projects such as this one, HEAL is catalyzing the development of innovative drugs designed to diminish reliance on opioids while addressing chronic and acute pain safely and effectively.
Sanford Burnham Prebys Medical Discovery Institute, now celebrating its 50th anniversary, continues to be at the forefront of biomedical research focused on fundamental human biology and translational science. The institute’s strength lies in its integrated centers of excellence across cancer, neuroscience, cardiovascular, metabolic, and liver diseases, complemented by cutting-edge capabilities in data science, artificial intelligence, and drug discovery. This environment fuels transformative discoveries with the potential to revolutionize health care globally.
Subject of Research: Development of a non-opioid pain therapeutic targeting neurotensin receptor 1 using biased allosteric modulation and structure-guided drug design.
Article Title: NIH HEAL Initiative Funds $3.9 Million to Propel Non-Addictive Pain Therapeutic Toward Clinical Trials
News Publication Date: 2025
Web References:
– NIH HEAL Initiative: https://heal.nih.gov/
– Cell Publication on SBI-810: https://www.cell.com/cell/abstract/S0092-8674(25)00508-2
– Nature Publication on SBI-553: https://www.nature.com/articles/s41586-025-09643-2
References: Research supported by NIH/NINDS Award Number UG3NS141745.
Image Credits: Sanford Burnham Prebys Medical Discovery Institute.
Keywords: Non-opioid pain treatment, neurotensin receptor 1, biased allosteric modulator, SBI-810, GPCR drug discovery, cryo-electron microscopy, artificial intelligence, medicinal chemistry, opioid epidemic, translational pharmacology, NIH HEAL Initiative, chronic pain.
Tags: artificial intelligence in pharmacologycollaborative pain research consortiumcryo-electron microscopy in drug designmedicinal chemistry optimizationNIH HEAL Initiative grantnon-opioid pain therapy developmentnovel analgesic drug discoveryopioid addiction alternative therapiesPhase 1 clinical trial pain treatmentreceptor signaling analysisSanford Burnham Prebys researchSBI-810 drug candidate
