Novel drug-like somatostatin receptor 4 agonists are potential analgesics for neuropathic pain

Boglárka Kántás, Rita Börzsei, Éva Szőke, Péter Bánhegyi, Ádám Horváth, Ágnes Hunyady, Éva Borbély, Csaba Hetényi, Erika Pintér, Zsuzsanna Helyes

Research output: Contribution to journalArticle

Abstract

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 µM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1–C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives.

Original languageEnglish
Article number6245
JournalInternational journal of molecular sciences
Volume20
Issue number24
DOIs
Publication statusPublished - Dec 2 2019

Keywords

  • Anti-hyperalgesic
  • Docking
  • G-protein activation
  • Inflammatory pain
  • Molecular modeling
  • Neurogenic inflammation
  • Neuropathic pain
  • Resiniferatoxin
  • Sst receptor

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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