# Structural elucidation and development of agonists for the human orexin receptors

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $556,297

## Abstract

The goal of this proposal is to gain a biophysical understanding of human orexin receptor agonist
binding and activation, and to use this knowledge to develop small-molecule orexin receptor agonists as
neuropharmacological tools and potential therapeutics for narcolepsy/cataplexy and other diseases.
Narcolepsy is a life-long debilitating disorder affecting approximately 200,000 Americans, which is
characterized by an inability to maintain wakefulness, sleep attacks, sudden loss of muscle function, and sleep
paralysis. Current treatments for narcolepsy (such as psychostimulant drugs) do not treat the underlying
neurochemical deficits and exhibit undesirable side-effects. Animal models and clinical investigations of human
patients show that narcolepsy is caused by deficiency of the orexin (hypocretin) neuropeptides produced by
neurons of the lateral hypothalamus, and that exogenous replacement of orexin activity may cure the disease.
However, orexins cannot be used as therapeutic agents because they are peptides, which do not penetrate the
blood-brain barrier and show poor activity after oral administration due to metabolic decomposition.
 We propose to use new technical advances in GPCR structural biology to determine X-ray structures of
the orexin receptors in orexin-bound and small-molecule agonist-bound states, revealing the detailed non-
covalent interactions that stabilize these complexes as well as changes in conformation of the receptors that
are a consequence of agonist binding. In the second Aim, we will develop conformation-specific nanobodies
that bind and stabilize the orexin receptor active state, and solve nanobody co-crystal structures to understand
the propagated structural changes across the membrane that link the extracellular neuropeptide binding site
and the intracellular G protein coupling site. In the third Aim, we will integrate structural insights with
computational docking/simulation and medicinal chemistry to improve the affinity and potency of small-
molecule orexin receptor agonists that were previously identified in a high-throughput screen. Our combination
of strengths in GPCR structural biology, synthetic and medicinal chemistry, and computational chemistry
places us in a unique position to design small-molecule orexin mimics with drug-like properties that can be
further developed into therapeutics for the treatment of narcolepsy and other neurological disorders.

## Key facts

- **NIH application ID:** 10241919
- **Project number:** 5R01NS103939-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JEF KAREL DE BRABANDER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $556,297
- **Award type:** 5
- **Project period:** 2017-09-30 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241919

## Citation

> US National Institutes of Health, RePORTER application 10241919, Structural elucidation and development of agonists for the human orexin receptors (5R01NS103939-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241919. Licensed CC0.

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