# Discovering Small Molecule Biased Agonists for the Neuropeptide S Receptor

> **NIH NIH R01** · RESEARCH TRIANGLE INSTITUTE · 2020 · $44,537

## Abstract

Anxiety disorders that are linked to events or things (e.g. post-traumatic stress disorder (PTSD), phobias)
would benefit from the simultaneous mitigation of the anxiety as well as the memories associated with the
inducing event. Although currently available anxiolytics are able to treat acute anxiety, they have been shown
to impair the formation of new memories. The symptoms of some anxiety disorders respond to acute and fast
acting benzodiazepines (e.g. initial and short-term treatment of panic disorder and generalized anxiety
disorder). However, others, such as PTSD, have persistent, highly intrusive symptoms (flashbacks) that are
resistant to current treatments. Moreover, PTSD has high comorbidity with depression, suicide, and drug
abuse, which are themselves difficult to treat especially in the presence of a debilitating anxiety disorder. A
selective pharmacotherapy that can both reduce anxiety within therapy sessions and is memory enhancing is
lacking. The neuropeptide S system has one endogenous ligand (NPS) and one receptor (NPSR) whose
expression is relatively restricted. The therapeutic potential for the NPS-system resides in its unique behavioral
profile, which is distinct from most systems. Central administration of NPS in mice enhances learning,
increases arousal and produces anxiolytic-like effects. Discovery of small molecule NPSR agonists, let alone
biased agonists has been extremely difficult. To our knowledge, no small molecule agonists have been
disclosed in the patent or peer reviewed literature. Based on research conducted in our lab, we have identified
the first and only biased, small molecule, NPS scaffold that retains full agonist properties in calcium
mobilization assays, but has attenuated ability to increase cAMP levels. This is distinct from the native peptide
(NPS) that displays roughly equal efficacy for both second messenger pathways. One of our biased agonists
produces similar anxiolytic and memory enhancing effects as NPS in mice and can be blocked with RTI-118 a
potent NPS antagonist. Based on this data we hypothesize biased agonists of the neuropeptide S receptor
(NPSR) lacking cAMP activation will be useful for treating PTSD and other anxiety disorders where memory
promotion is beneficial. The chemistry component of this application aims to improve NPSR potency, maintain
signaling bias, and enhance drug-like properties of the lead compounds. The behavioral component of the
application will focus on further establishing the behavioral profiles for our biased agonists. These aims will be
accomplished through a collaboration of chemistry, in vitro pharmacology, and behavioral pharmacology
programs.

## Key facts

- **NIH application ID:** 10072170
- **Project number:** 3R01MH122196-01S1
- **Recipient organization:** RESEARCH TRIANGLE INSTITUTE
- **Principal Investigator:** Stewart Donaldson Clark
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $44,537
- **Award type:** 3
- **Project period:** 2020-03-06 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072170

## Citation

> US National Institutes of Health, RePORTER application 10072170, Discovering Small Molecule Biased Agonists for the Neuropeptide S Receptor (3R01MH122196-01S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10072170. Licensed CC0.

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