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Bioorg Med Chem. 2017 Jan 1;25(1):350-359. doi: 10.1016/j.bmc.2016.10.039. Epub 2016 Nov 1.

NTS2-selective neurotensin mimetics with tetrahydrofuran amino acids.

Author information

1
Faculty of Chemistry and Pharmacy, Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
2
Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen Nürnberg (FAU), Schuhstr. 19, 91052 Erlangen, Germany; Institute of Physiology, Paracelsus Medical University Nürnberg, 90419 Nürnberg, Germany.
3
Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen Nürnberg (FAU), Schuhstr. 19, 91052 Erlangen, Germany.
4
Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen Nürnberg (FAU), Schuhstr. 19, 91052 Erlangen, Germany. Electronic address: peter.gmeiner@fau.de.
5
Faculty of Chemistry and Pharmacy, Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany. Electronic address: burkhard.koenig@ur.de.

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

PMID:
27842797
DOI:
10.1016/j.bmc.2016.10.039
[Indexed for MEDLINE]

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