Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 21, Pages 12929-12941Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01376
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Funding
- Austrian Research Fund [FWF: I2463-B21]
- Research Foundation Flanders (FWO Vlaanderen)
- Canadian Institutes of Health Research (CIHR) [FDN148413]
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2014-06358]
- Canada Research Chair in Neurophysiopharmacology of Chronic Pain
- FRQ-S
- University of Innsbruck PhD stipend program
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Fusion of nonopioid pharmacophores, such as neurotensin, with opioid ligands represents an attractive approach for pain treatment. Herein, the mu-/delta-opioid agonist tetrapeptide H-Dmt-D-Arg-Aba-beta-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 beta(3)-homo amino acid in position 8 and Tyr(11) substitutions. Combination of beta(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 mu M), 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.
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