Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure−Activity Relationship Studies - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2020

Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure−Activity Relationship Studies

Résumé

Fusion of nonopioid 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-NH 2 (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 β 3-homo amino acid in position 8 and Tyr 11 substitutions. Combination of β 3 hArg and Dmt led to peptide 7, a MOR agonist, showing the highest NTS2 affinity described to date (K i = 3 pM) and good NTS1 affinity (K i = 4 nM), providing a >1300-fold NTS2 selectivity. The (6-OH)Tic-containing analogue 9 also exhibited high NTS2 affinity (K i = 1.7 nM), with low NTS1 affinity (K i = 4.7 μM), resulting in an excellent NTS2 selectivity (>2700). In mice, hybrid 7 produced significant and prolonged antinociception (up to 8 h), as compared to the KGOP01 opioid parent compound.
Fichier principal
Vignette du fichier
Gonzalez et al revised JMC 250820 UNMARKED Final.pdf (1.13 Mo) Télécharger le fichier
Origine Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03150260 , version 1 (01-03-2021)

Identifiants

Citer

Simon Gonzalez, Maria Dumitrascuta, Emilie Eiselt, Stevany Louis, Linda Kunze, et al.. Optimized Opioid-Neurotensin Multitarget Peptides: From Design to Structure−Activity Relationship Studies. Journal of Medicinal Chemistry, 2020, 63 (21), pp.12929-12941. ⟨10.1021/acs.jmedchem.0c01376⟩. ⟨hal-03150260⟩
96 Consultations
1 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More