NTS2-selective neurotensin mimetics with tetrahydrofuran amino acids
| Autor: | Harald Hübner, Manuel Bause, Peter Gmeiner, Jürgen Einsiedel, Michael Dobmeier, Daniel Lachmann, Burkhard König, Nadja A. Simeth, Ralf C. Kling |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Peptidomimetic Stereochemistry Clinical Biochemistry Molecular Conformation Pharmaceutical Science Peptide CHO Cells Molecular Dynamics Simulation Biochemistry 03 medical and health sciences chemistry.chemical_compound Cricetulus 0302 clinical medicine Drug Discovery Animals Humans Receptors Neurotensin Neurotensin receptor Binding site Furans Molecular Biology Neurotensin chemistry.chemical_classification Binding Sites Peptide analog Molecular Mimicry Organic Chemistry Peptide Fragments Pyrrolidonecarboxylic Acid Amino acid HEK293 Cells 030104 developmental biology chemistry Molecular Medicine Peptidomimetics Selectivity 030217 neurology & neurosurgery |
| Zdroj: | Bioorganic & Medicinal Chemistry. 25:350-359 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2016.10.039 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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