Abstract
Stimulation of the NTS2 neurotensin receptor causes antipsychotic effects and leads to a promotion of the μ-opioid-independent antinociception, which is important in the modulation of tonic pain sensitivity. We report the synthesis and properties of a small library of peptidic agonists based on the active neurotensin fragment NT(8-13). Two tetrahydrofuran amino acid derivatives were synthesized to replace Tyr11 in NT(8-13). Additionally, Arg8, Arg9, and Ile12 of the lead peptide were exchanged by Lys, Lys, and Gly, respectively. The new compounds showed substantial NTS2 binding affinity and up to 1000-fold selectivity over NTS1. The highest selectivity (Ki(NTS2): 29nM, Ki(NTS1): 35,000nM) was observed for the peptide analog 17Rtrans.
Keywords:
Neurotensin; Non-natural amino acid; Peptides.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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CHO Cells
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Cricetulus
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Furans / chemical synthesis
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Furans / chemistry
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Furans / pharmacology*
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HEK293 Cells
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Humans
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Molecular Conformation
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Molecular Dynamics Simulation
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Molecular Mimicry
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Neurotensin / chemical synthesis
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Neurotensin / chemistry
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Neurotensin / pharmacology*
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Peptide Fragments / chemical synthesis
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Peptide Fragments / chemistry
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Peptide Fragments / pharmacology*
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Peptidomimetics / chemical synthesis
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Peptidomimetics / chemistry
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Peptidomimetics / pharmacology*
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Pyrrolidonecarboxylic Acid / analogs & derivatives*
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Pyrrolidonecarboxylic Acid / chemical synthesis
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Pyrrolidonecarboxylic Acid / chemistry
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Pyrrolidonecarboxylic Acid / pharmacology
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Receptors, Neurotensin / agonists*
Substances
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Furans
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NTSR2 protein, human
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Peptide Fragments
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Peptidomimetics
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Receptors, Neurotensin
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neurotensin type 1 receptor
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Neurotensin
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neurotensin (1-8)
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Pyrrolidonecarboxylic Acid