Lieber Institute Researchers Develop a New Kind of Benzodiazepine Candidate Designed to Quiet Gut Pain - Without Entering the Brain
Baltimore, MD (Jan 06, 2026) — For millions of people living with irritable bowel syndrome (IBS), functional dyspepsia, and related visceral pain syndromes, chronic abdominal pain isn’t just uncomfortable, it can be relentless, unpredictable, and life-shaping. Yet many of the medicines that can meaningfully affect pain pathways come with a familiar tradeoff: they work on the brain, too, bringing sedation, cognitive impairment, and in some cases dependence risk.
A new study from researchers at the Lieber Institute for Brain Development (LIBD) describes a different approach: a benzodiazepine-like compound designed to work in the periphery – targeting pain-relevant signaling in sensory pathways connected to the gut – while minimizing entry into the central nervous system.
The paper, titled “Development of a Novel Benzodiazepine to Delineate Peripheral GABA-A Signaling Mechanisms in Visceral Pain Syndromes,” reports the design and preclinical testing of LI-633, a novel peripherally restricted positive allosteric modulator (PAM) of GABA-A receptors.
The study was led by co-senior and corresponding authors Jay Pankaj Pasricha, M.B.B.S., M.D., and James Barrow, Ph.D., with contributions from a cross-institutional team that included Lieber Institute scientists and collaborators at the Mayo Clinic, and Johns Hopkins University.
“Visceral pain syndromes like IBS and functional dyspepsia affect huge numbers of people, and too often the options are limited or come with unacceptable side effects,” said Jay Pankaj Pasricha, M.B.B.S., M.D. “This work explores whether we can target the biology of pain at the level of peripheral sensory signaling, without engaging the brain mechanisms that drive sedation and other central effects.”
A familiar drug class, re-engineered for a different destination
Benzodiazepines are widely known for their central nervous system effects, which include sedation and anxiolysis. They act on several subtypes of GABA-A receptors, and decades of research suggest that enhancing GABA-A signaling can influence pain processing. The core problem: most benzodiazepines cross the blood-brain barrier, making it difficult to isolate what’s happening in the periphery versus the brain and limiting their usefulness for chronic pain.
Researchers did something both practical and bold: they redesigned the scaffold.
Using medicinal chemistry optimization, the team engineered LI-633 to maintain potent GABA-A modulation while limiting central penetration. In pharmacokinetic studies in rats, the compound demonstrated minimal brain exposure, even at high doses, an important step toward separating peripheral activity from central side effects.
“Our goal was to develop a molecule that preserves the beneficial pharmacology of benzodiazepine-site modulation of GABA-A receptors, but with highly restricted access to the CNS,” said James Barrow, Ph.D. “That allowed us to test a clear hypothesis: if we enhance GABA-A signaling in peripheral sensory pathways, can we reduce visceral hypersensitivity without sedation?”
From neurons to behavior: converging evidence across models
To answer that question, the study included receptor pharmacology in cellular and living systems. LI-633 showed potent activity across several benzodiazepine-sensitive GABA-A receptor subtypes. The team then examined whether the compound could reduce excitability in nociceptive sensory neurons, which carry pain signals from peripheral tissues toward the spinal cord and brain.
In electrophysiological experiments, LI-633 was associated with reduced excitability in both rat and human dorsal root ganglion (DRG) neurons – a key translational link, given how often promising pain candidates fail to translate beyond animal models.
Next came the question patients care about most: does it change pain-related outcomes?
In two established preclinical models, one mimicking aspects of IBS-like visceral hypersensitivity and another modeling functional dyspepsia, LI-633 significantly reduced measures of visceral pain behavior and hypersensitivity. Importantly, the compound did not produce measurable sedation in an open-field locomotor assay at tested doses, consistent with its peripheral restriction.
Taken together, these results support a central conclusion: peripheral GABA-A receptors may represent viable analgesic targets for visceral pain, and peripherally acting GABA-A PAMs like LI-633 could open a path toward non-sedating, non-opioid approaches for chronic gastrointestinal pain syndromes. In particular, functional dyspepsia affects more than 10% of the US population and has no FDA approved treatment. Additionally, many patients with inflammatory bowel disease (IBD) that have been treated with biologics to reduce inflammation still have debilitating IBS-like symptoms.
A tool for discovery
The authors emphasize that LI-633 is both a potential lead compound and a tool for clarifying a longstanding biological question in gut-brain axis disorders: what portion of pain relief comes from modifying signaling in the gut and peripheral sensory pathways, and what portion is centrally mediated?
That distinction matters, not only for minimizing side effects, but for designing therapies that are targeted, tolerable, and compatible with chronic use.
“This is the kind of work that can shift how we think about symptom biology,” said Daniel R. Weinberger, M.D., Director and CEO of the Lieber Institute for Brain Development. “When we can separate peripheral mechanisms from central effects, we gain precision, scientifically and clinically. That precision is what ultimately helps the field move toward safer, more effective treatments.”
You can access the paper here.
About the Lieber Institute for Brain Development
The mission of the Lieber Institute for Brain Development and the Maltz Research Laboratories is to translate the understanding of basic genetic and molecular mechanisms of schizophrenia and related developmental brain disorders into clinical advances that change the lives of affected individuals. LIBD is an independent, not-for-profit 501(c)(3) organization and a Maryland tax-exempt medical research institute affiliated with the Johns Hopkins University School of Medicine. The Lieber Institute’s brain repository of nearly 5,000 human brains is the largest collection of postmortem brains for the study of neuropsychiatric disorders worldwide.
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Media Contact: Oluwaseyi Abujade, media@libd.org