Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain
| Autor: | Ágnes Hunyady, Ádám Horváth, Boglárka Kántás, Csaba Hetényi, Éva Borbély, Erika Pintér, Péter Bánhegyi, Éva Szőke, Rita Börzsei, Zsuzsanna Helyes |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
sst4 receptor Analgesic Administration Oral CHO Cells G-protein activation Pharmacology Molecular Dynamics Simulation Ligands Catalysis Article Inorganic Chemistry Mice Cricetulus Oral administration In vivo Cricetinae Medicine Animals Pyrroles Receptors Somatostatin Physical and Theoretical Chemistry Receptor Molecular Biology Spectroscopy inflammatory pain Inflammation neuropathic pain Neurogenic inflammation Analgesics neurogenic inflammation Somatostatin receptor business.industry molecular modeling Organic Chemistry resiniferatoxin anti-hyperalgesic General Medicine Computer Science Applications Somatostatin Pyrimidines Hyperalgesia Neuropathic pain Chronic Disease docking Neuralgia Diterpenes business |
| Zdroj: | International Journal of Molecular Sciences Volume 20 Issue 24 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms20246245 |
| Popis: | 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 &mu M), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1&ndash 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 (&gamma 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 µ g/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 µ g/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. |
| Databáze: | OpenAIRE |
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