Somatostatin receptor-4 (SST4) is a therapeutic target for several conditions, including Alzheimer’s disease, seizures, neuropsychiatric disorders, and pain. Our previous work on 1,2,4-triazole derivatives led to enhanced SST4 binding affinity, selectivity, and functional activity. Herein we report the discovery of 3-thio-1,2,4-triazole series as selective and high affinity SST4 agonists. Thirty-three compounds show 300-fold selectivity over other SST subtypes. SST4 cAMP inhibition assay activity data aligned with the ligand binding affinity. Comparative docking results of the ligands under investigation with the cryo-EM and most recent model-built SST4 structures suggest similar trends in binding. Amino acids responsible for high and moderate affinity were identified, whereas poorer ligand conformations and limited interactions were observed with the low-affinity compounds. In summary, this study presents a novel series of high affinity SST4 agonists with corresponding in vitro activity, demonstrating viable therapeutic potential.
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