# Parallel Multimodal High-throughput screening to identify activators of the orexin receptors

> **NIH NIH R01** · SCRIPPS FLORIDA · 2020 · $731,424

## Abstract

PROJECT SUMMARY
 The GPCR superfamily of ligand regulated receptors has proven to be a rich source of targets for
development of therapeutics for a myriad of human diseases. The orexin 1 and orexin 2 receptors are class A
GPCR’s differentially expressed in the central nervous system. The orexin 1 receptor is most abundantly
expressed in the locus coeruleus and is thought to control aspects of emotion, reward, and the autonomic
nervous system, whereas the orexin 2 receptor is expressed in regions controlling arousal such as the
tubermammillary nucleus, an important site for the regulation of sleep/wakefulness. Almost 20 years after their
initial discovery, the first potent dual orexin 1 / orexin 2 receptor antagonist therapeutic has been brought to
market for insomnia (Belsomera ®, suvorexant, Merck). Despite a massive effort to identify antagonists of the the
orexin receptor, almost no reports of small molecule agonists appear in the primary or patent literature. Elegant
genetic ablation experiments using orexin knock-out animals and experiments with intracerebroventricular dosing
of orexin A or orexin B peptides suggests a role for orexin receptor agonists or potentiators for a number of potential
indications including: 1) depression; 2) learning and memory (cognition); 3) attention deficit hyperactivity disorder
(ADHD); 4) treatment for colon cancer; and 5) sleep disorders including narcolepsy. While the orexin peptides are
potent agonists of both orexin receptors, they are not selective nor do they cross the blood brain barrier well,
making them poor probe substrates for in vivo pharmacology studies. This provides the impetus to identify small
molecule, brain penetrant activators of the orexin receptors to interrogate the receptors function in the context of
disease states. We have optimized a cell-based high-throughput screening compatible primary assay that
specifically measures the functional activity of orexin 1 and orexin 2. A preliminary 10k pilot screen was
performed leading to the identification of a number of small molecule agonists of these receptors demonstrating
this assay to be robust and reproducible. A full HTS screening campaign of the Scripps Institutional Drug
Discovery Library (~640k compounds) will lead to the identification of multiple classes of orexin receptor agonists
and potentiators for further development. In an iterative process, these validated hits will be characterized
through a cascade of in vitro cell-based assays to determine potency, selectivity and mechanism of action.
Preliminary medicinal chemistry lead optimization will identify early structure activity relationships and in vitro
drug metabolism will be assessed to confirm tractibility of early leads. These efforts will provide first in-class
chemical tools to be used to further probe orexin receptor function in animal models of disease.

## Key facts

- **NIH application ID:** 9891102
- **Project number:** 5R01MH117499-03
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Theodore M Kamenecka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $731,424
- **Award type:** 5
- **Project period:** 2018-07-05 → 2022-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891102

## Citation

> US National Institutes of Health, RePORTER application 9891102, Parallel Multimodal High-throughput screening to identify activators of the orexin receptors (5R01MH117499-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9891102. Licensed CC0.

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