20.500.12556/RUL-182063 Trifluoromethylthio and trifluoromethyl functionalization of endomorphin-1 enhances its hydrophobicity and plasma stability while preserving its affinity for the $\mu$-opioid receptor The incorporation of fluorinated amino acid residues into peptides represents a promising strategy for improving the pharmacokinetic properties of bioactive peptides. Herein, we report the solid-phase synthesis (SPPS) of a set of ten SCF$_{3^-}$ or CF$_{3^-}$ modified neuropeptide analogs based on endomorphin-1 (EM1). EM1, a selective subnanomolar μ-opioid receptor (μOR) agonist with poor metabolic stability (t$_{1/2}$ = 6 min in human plasma), was selected as a model to evaluate the effects of SCF$_3$ and CF$_3$ functionalization on the pharmacokinetic profile of short bioactive peptides. The syntheses of eight ready-to-use SCF$_{3^-}$ or CF$_{3^-}$ containing building blocks for SPPS and their incorporation into peptides are reported. In vitro μOR binding and functional activity assays demonstrated that most fluorinated analogs retained binding affinity and potency, accompanied by increased hydrophobicity. Among the series, modification of the pharmacophoric Tyr1 residue with l-Dmt(3-SCF$_3$) yielded the most favorable profile (K$_i$ = 1.4 nM, EC$_{50}$ = 0.9 nM). Plasma stability studies revealed a significant increase in half-life for this ligand (72-fold relative to EM1 and 14-fold relative to EM1(Dmt$^1$)), and thus, further demonstrated the potential of SCF$_{3^-}$containing amino acids in therapeutic peptide design. ligands peptides opioid receptors fluorine metabolic stability ligandi peptidi opioidni receptorji fluor metabolna stabilnost true false true Angleški jezik Slovenski jezik Članek v reviji 2026-04-23 14:06:37 2026-04-23 14:06:39 2026-05-06 04:29:04 0000-00-00 00:00:00 2026 0 0 Str. 5598-5607 iss. 16 Vol. 91 24 Apr. 2026 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 547.9:546.16 0022-3263 10.1021/acs.joc.6c00321 276208643 RAZ_Gregorc_Jure_2026.pdf RAZ_Gregorc_Jure_2026.pdf 1 3DF732D37A8B5A6EC545E99C48A9B0B6 9109fe5bb6b44317e1a71820dd96c6ed45bc50da2428d707d35d13cbbe812c8f fed08343-4857-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=233325 https://pubs.acs.org/doi/10.1021/acs.joc.6c00321 1 a402b146-3f0c-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=232996 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0