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. 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

Nadja A Simeth  1 , Manuel Bause  1 , Michael Dobmeier  1 , Ralf C Kling  2 , Daniel Lachmann  1 , Harald Hübner  3 , Jürgen Einsiedel  3 , Peter Gmeiner  4 , Burkhard König  5
Affiliations

NTS2-selective neurotensin mimetics with tetrahydrofuran amino acids

Nadja A Simeth et al. Bioorg Med Chem. .

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.

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