C-terminal modified Enkephalin-like tetrapeptides with enhanced affinities at the kappa opioid receptor and monoamine transporters.
Analgesics
Monoamine neurotransmitter-uptake inhibitors
Multifunctional ligands
Opioids
Synergistic effect
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
received:
12
07
2021
revised:
11
10
2021
accepted:
15
10
2021
pubmed:
20
11
2021
medline:
19
1
2022
entrez:
19
11
2021
Statut:
ppublish
Résumé
A new series of enkephalin-like tetrapeptide analogs modified at the C-terminus by an N-(3,4-dichlorophenyl)-N-(piperidin-4-yl)propionamide (DPP) moiety were designed, synthesized, and tested for their binding affinities at opioid receptors and monoamine transporters to evaluate their potential multifunctional activity for the treatment of chronic pain. Most ligands exhibited high binding affinities in the nanomolar range at the opioid receptors with a slight delta-opioid receptor (DOR) selectivity over mu-opioid receptor (MOR) and kappa-opioid receptor (KOR) and low binding affinities in the micromolar range at the monoamine transporters, SERT and NET. Ligands of which the positions 1 and 4 were substituted by Dmt and Phe(4-X) residues, respectively, showed the excellent binding affinities at three opioid receptors. Among them, Dmt-d-Tic-Gly-Phe(4-F)-DPP was the most promising considering its excellent opioid affinities, particularly unexpected high binding affinity (Ki = 0.13 nM) at the KOR, and moderate interactions with serotonin/norepinephrine reuptake inhibitors (SNRIs). Docking studies revealed that the ligand was a good fit for the KOR binding pocket (binding score = 8,750).
Identifiants
pubmed: 34798381
pii: S0968-0896(21)00517-4
doi: 10.1016/j.bmc.2021.116509
pmc: PMC8649046
mid: NIHMS1759033
pii:
doi:
Substances chimiques
Amides
0
Ligands
0
Oligopeptides
0
Receptors, Opioid, kappa
0
Receptors, Opioid, mu
0
propionamide
QK07G0HP47
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
116509Subventions
Organisme : NIDA NIH HHS
ID : P01 DA006284
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Ltd. All rights reserved.
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