Comparative evaluation for small molecule somatostatin 4 receptor agonists: in silico, in vitro, and in vivo approaches

Biskup, Dóra and Ganbold, Minjin and Nehr-Majoros, Andrea Kinga and Tékus, Valéria and Hajna, Zsófia Réka and Fülöp, Barbara and Szőke, Éva and Hetényi, Csaba and Crider, A.M. and Daryaei, I. and Helyes, Zsuzsanna and Börzsei, Rita and Pintér, Erika (2026) Comparative evaluation for small molecule somatostatin 4 receptor agonists: in silico, in vitro, and in vivo approaches. FRONTIERS IN PHARMACOLOGY, 17. ISSN 1663-9812

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Abstract

Introduction:The treatment of neuropathic pain with traditional and adjuvant analgesics is limited in efficacy and associated with severe adverse effects. Our group has previously shown that somatostatin, released from capsaicin-sensitive peptidergic sensory nerve terminals, mediates analgesic and anti-inflammatory effects at the peripheral and central levels via the somatostatin receptor subtype 4 (SST4). The therapeutic use of native somatostatin is limited by its numerous biological actions mediated by the five somatostatin receptors and its short elimination half-life. Therefore, the development of SST4-selective agonists may be an effective approach for treating neuropathic pain. Methods: In this comparative study, the receptor binding and activation properties of four small molecules were compared with those of somatostatin and the SST4 receptor superagonist, J-2156, through in silico drug-likeness investigation, pharmacokinetic prediction, molecular docking calculations, in vitro cAMP accumulation assays, and in vivo assessment of their antihyperalgesic effects in the partial sciatic nerve ligation mouse model of traumatic neuropathy. Results and Discussion: Docking calculations showed that all compounds interact with the conserved Asp126 of SST4, which is suggested to play a key role in ligand binding. cAMP assays confirmed that all molecules activate the SST4 receptor with comparable potency to that of J-2156. All examined compounds reversed PSNL-induced mechanical hyperalgesia. Their antihyperalgesic effects ranged from 20% to 70% and depended on both the time and the applied dose. These results suggest that the tested compounds could be potentially effective in the treatment of neuropathic pain.

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