PN6047 demonstrates preclinical efficacy in headache models as a novel delta-opioid receptor agonist
5 affiliations
- 1Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, 2 Pharmacy Pl., St. Louis, MO 63110 USA
- 2Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA USA
- 3Department of Pharmacology, University of Virginia, Charlottesville, VA USA
- 4Edward F. Domino Research Center, Department of Pharmacology, University of Michigan, Ann Arbor, MI USA
- 5PharmNovo AB, Lund, Sweden
Abstract
Background: The Delta-opioid receptor (DOR) has gained attention as a promising target for the treatment of migraine and headache disorders. This is largely attributed to its unique pharmacological profile, which suggests that DOR-targeting treatment offers effective therapeutic effect with a lower risk of medication-overuse headache (MOH), reduced abuse liability, and minimal potential for physical dependence. These advantages have driven the development of a novel DOR agonist PN6047 (3-[[4-(dimethylcarbamoyl) phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene] methyl]benzamide), which has completed Phase I clinical trial and showed a favorable safety and tolerability profile. Although PN6047 has shown promising effects in neuropathic pain models, its efficacy in preclinical models of headache-associated pain remains to be evaluated. Here, we investigated the effects of PN6047 in models of migraine-associated pain and aura as well as post-traumatic headache (PTH) and MOH.
Methods: C57BL/6J mice were used to examine the effects of PN6047 in the following migraine models: chronic intermittent nitroglycerin (NTG)-induced migraine-associated pain, PTH, KCl-induced cortical spreading depression (CSD), and optogenetic evoked CSD in freely behaving transgenic mice expressing ChR2-eYFP. In addition, we tested whether chronic PN6047 induced MOH and whether it could prevent the development of MOH induced by sumatriptan.
Results: A single injection of PN6047 blocked chronic cephalic allodynia established by chronic intermittent NTG and PTH. Moreover, chronic PN6047 treatment prevented the development of MOH induced by sumatriptan, without causing MOH itself. In addition, PN6047 significantly reduced the number of CSD events in the KCl-induced CSD model, and delayed CSD onset triggered in freely behaving mice along with subsequent CSD-evoked allodynia.
Conclusion: PN6047, a novel DOR agonist, attenuates headache-associated mechanisms and symptoms in preclinical models of chronic migraine, migraine aura, PTH, and MOH. Importantly, prolonged PN6047 treatment did not induce MOH or analgesic tolerance. Together, these data demonstrate that despite the distinct mechanisms underlying migraine and headache disorder models, PN6047 exhibits significant efficacy without inducing MOH, and displays a favorable safety and tolerability profile.
Clinical trial number: Not applicable.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s10194-026-02473-1.
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BibTeX
@article{awadigbaria2026pn6047,
title = {{PN6047 demonstrates preclinical efficacy in headache models as a novel delta-opioid receptor agonist}},
author = {Yaseen Awad-Igbaria and Yanping Zhang and Mattin Aframian and Guido C. Faas and Andrew Charles and Serapio M. Baca and Emily Jutkiewicz and Bengt von Mentzer and John Traynor and David Kendall and Amynah A. Pradhan},
journal = {The Journal of Headache and Pain},
year = {2026},
month = aug,
doi = {10.1186/s10194-026-02473-1},
url = {https://doi.org/10.1186/s10194-026-02473-1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - PN6047 demonstrates preclinical efficacy in headache models as a novel delta-opioid receptor agonist
AU - Yaseen Awad-Igbaria
AU - Yanping Zhang
AU - Mattin Aframian
AU - Guido C. Faas
AU - Andrew Charles
AU - Serapio M. Baca
AU - Emily Jutkiewicz
AU - Bengt von Mentzer
AU - John Traynor
AU - David Kendall
AU - Amynah A. Pradhan
PY - 2026
DA - 2026/08/06
JO - The Journal of Headache and Pain
DO - 10.1186/s10194-026-02473-1
UR - https://doi.org/10.1186/s10194-026-02473-1
AB - Background: The Delta-opioid receptor (DOR) has gained attention as a promising target for the treatment of migraine and headache disorders. This is largely attributed to its unique pharmacological profile, which suggests that DOR-targeting treatment offers effective therapeutic effect with a lower risk of medication-overuse headache (MOH), reduced abuse liability, and minimal potential for physical dependence. These advantages have driven the development of a novel DOR agonist PN6047 (3-[[4-(dimethylcarbamoyl) phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene] methyl]benzamide), which has completed Phase I clinical trial and showed a favorable safety and tolerability profile. Although PN6047 has shown promising effects in neuropathic pain models, its efficacy in preclinical models of headache-associated pain remains to be evaluated. Here, we investigated the effects of PN6047 in models of migraine-associated pain and aura as well as post-traumatic headache (PTH) and MOH. Methods: C57BL/6J mice were used to examine the effects of PN6047 in the following migraine models: chronic intermittent nitroglycerin (NTG)-induced migraine-associated pain, PTH, KCl-induced cortical spreading depression (CSD), and optogenetic evoked CSD in freely behaving transgenic mice expressing ChR2-eYFP. In addition, we tested whether chronic PN6047 induced MOH and whether it could prevent the development of MOH induced by sumatriptan. Results: A single injection of PN6047 blocked chronic cephalic allodynia established by chronic intermittent NTG and PTH. Moreover, chronic PN6047 treatment prevented the development of MOH induced by sumatriptan, without causing MOH itself. In addition, PN6047 significantly reduced the number of CSD events in the KCl-induced CSD model, and delayed CSD onset triggered in freely behaving mice along with subsequent CSD-evoked allodynia. Conclusion: PN6047, a novel DOR agonist, attenuates headache-associated mechanisms and symptoms in preclinical models of chronic migraine, migraine aura, PTH, and MOH. Importantly, prolonged PN6047 treatment did not induce MOH or analgesic tolerance. Together, these data demonstrate that despite the distinct mechanisms underlying migraine and headache disorder models, PN6047 exhibits significant efficacy without inducing MOH, and displays a favorable safety and tolerability profile. Clinical trial number: Not applicable. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s10194-026-02473-1.
SN - 1129-2369
SN - 1129-2377
ER -