Dual Opioid–Neuropeptide FF Small Molecule Ligands Demonstrate Analgesia with Reduced Tolerance Liabilities
Marco Mottinelli, V. Blair Journigan, Samuel Obeng, Victoria L. C. Pallares, Christophe Mѐsangeau, Coco N. Kapanda, Stephen J. Cutler, Janet A. Lambert, Shainnel O. Eans, Michelle L. Ganno, Wanhui Sheng, Tamara King, Abhisheak Sharma, Catherine Mollereau, Bonnie A. Avery
TL;DR
A new type of painkiller that combines opioid and neuropeptide FF effects shows strong pain relief with less tolerance and fewer side effects.
Contribution
Dual-action opioid–NPFF ligands demonstrate analgesia with reduced tolerance and side effects compared to morphine.
Findings
Compound 22b showed dose-dependent antinociception with an ED50 of 6.88 nmol.
22b prevented NPFF-induced hyperalgesia and avoided morphine-like side effects.
Repeated treatment with 22b caused significantly less tolerance than morphine.
Abstract
Neuropeptide FF (NPFF) receptor antagonists prevent morphine-mediated antinociceptive tolerance, and compounds with dual mu opioid receptor (MOR) agonist and NPFF antagonist activity produce antinociception without tolerance. Compounds synthesized showed affinities in radioligand competition binding assays in the nM and µM range at the opioid and NPFF receptors, respectively, and displayed substitution-dependent functional profiles in the [35S]GTPγS functional assay. From six compounds screened in vivo for antinociception and ability to prevent NPFF-induced hyperalgesia in mouse warm water tail withdrawal tests, compound 22b produced dose-dependent MOR-mediated antinociception with an ED50 value (and 95% confidence interval) of 6.88 (4.71–9.47) nmol, i.c.v., and also prevented NPFF-induced hyperalgesia. Meanwhile, 22b did not demonstrate the respiratory depression, hyperlocomotion, or…
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Taxonomy
TopicsReceptor Mechanisms and Signaling · Neuropeptides and Animal Physiology · Pharmacological Receptor Mechanisms and Effects