Simon Gonzalez, Maria Dumitrascuta, Emilie Eiselt, Stevany Louis, Linda Kunze, Annalisa Blasiol, Mélanie Vivancos, Santo Previti, Elke Dewolf, Charlotte Martin, Dirk Tourwè, Florine Cavelier, Louis Gendron, Philippe Sarret, Mariana Spetea, Steven Ballet
Fusion of non-opioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the µ-/δ-opioid agonist tetrapeptide H-Dmt-D-Arg-Aba-β-Ala-NH2 (KGOP01) was fused to NT(8-13) analogues. Since the NTS1 receptor has been linked to adverse effects, selective MOR-NTS2 ligands are preferred. Modifications were introduced within the native NT sequence, particularly a β3-homo amino acid in position 8 and Tyr11 substitutions. Combination of β3hArg and Dmt led to peptide 7, a MOR agonist, displaying the highest NTS2 affinity described to date (Ki = 3 pM) and good NTS1 affinity (Ki = 4 nM), providing a >1300-fold NTS2 selectivity...
September 9, 2020: Journal of Medicinal Chemistry