# Discovery of non-addictive KOR antagonists for migraine prophylaxis

> **NIH NIH UH3** · BLACKTHORN THERAPEUTICS, INC. · 2020 · $110,635

## Abstract

   
DESCRIPTION (provided by applicant): Migraine is the world's most common neurological disorder. This condition is characterized by a number of phases including a prodrome, the headache phase and a post-drome. In the headache phase, disabling cephalic pain occurs that is typically unilateral and persists for 4-72 hours. The migraine attack is also often associated with nausea, vomiting and hypersensitivity to a variety of external stimuli including light and sound. The International Headache Society distinguishes migraine without aura (MO) and migraine with aura (MA). The pathophysiology of migraine is not well understood but ultimately, migraine is believed to arise from a state of altered cortical excitability (dysexcitability) capabe of activating the trigeminovascular system in genetically susceptible individuals. One of the most commonly noted clinical triggers of migraine is stress. How stress may trigger migraine is unknown. Recent evidence suggests that stress activates the dynorphin/KOR system to produce multiple CNS effects. Our preliminary data suggest that stress can induce features that are consistent with clinical observations of migraine in a novel animal model of medication overuse headache (MOH) induced by a period of exposure to triptan drugs. In this proposal, we plan to discover a brain penetrant kappa opioid receptor (KOR) antagonist that can be developed for the prophylactic treatment of migraine. We will synthesize and optimize compounds from a preliminary scaffold, characterize them in vitro for their receptor selectivity, and evaluate them for harmacodynamics (PD), pharmacokinetic (PK), metabolic, side-effect and safety profiles in vivo. The first specific aim will synthesize and perform in vitro assays of novel 4-amine-N-(quinolyn-2- yl)piperidines. The second specific aim will assess the DMPK characteristics of these novel compounds. Aim 3 will characterize CYM51317, a prototype KOR antagonist, in migraine prevention in our rat MOH model and screen novel KOR antagonists for migraine prophylaxis to identify new molecules that have drug-like profiles that will enable IND-filing. These studies will allow identification of a candidate molecule that can be pursued for human evaluation.

## Key facts

- **NIH application ID:** 10011866
- **Project number:** 5UH3NS093030-05
- **Recipient organization:** BLACKTHORN THERAPEUTICS, INC.
- **Principal Investigator:** Lori Jean Van Orden
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $110,635
- **Award type:** 5
- **Project period:** 2015-09-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011866

## Citation

> US National Institutes of Health, RePORTER application 10011866, Discovery of non-addictive KOR antagonists for migraine prophylaxis (5UH3NS093030-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10011866. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*