Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)‐Selective Peptide–Peptoid Hybrids |
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Authors: | Dr. Cornelia Held Dr. Harald Hübner Ralf Kling Dr. Yvonne A. Nagel Prof. Dr. Helma Wennemers Prof. Dr. Peter Gmeiner |
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Affiliation: | 1. Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstra?e 19, 91052 Erlangen (Germany);2. ETH Zürich, Laboratory for Organic Chemistry, Wolfgang Pauli Strasse 10, 8093, Zürich (Switzerland) |
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Abstract: | To investigate the binding mode and structure–activity relationships (SARs) of selective neurotensin receptor 2 (NTS2) ligands, novel peptide–peptoid hybrids that simulate the function of the endogenous ligand were developed. Starting from our recently described NTS2 ligands of type 1 , structural variants of type 2 and the metabolically stable analogues 3 a , b were developed. Replacement of the proline unit by a collection of structural surrogates and evaluation of the respective molecular probes for NTS2 affinity and selectivity indicated similar SARs as described for NT(8–13) derivatives bound to the subtype NTS1. Peptide–peptoid hybrids 2 d , 3 a , b showed substantial NTS2 binding affinity (Ki=8.1–16 nM ) and 2400–8600‐fold selectivity over NTS1. The thiazolidine derivative 3 b showed metabolic stability over 32 h in a serum degradation assay. In an inositol phosphate accumulation assay, the neurotensin mimetics 3 a and 3 b displayed an inhibition of constitutive activity exceeding 1.7–2.0 times the activity of NT(8–13). The fluorinated derivative 3 a could afford attractive opportunities to detect NTS2 by 19F magnetic resonance imaging. |
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Keywords: | GPCRs neurotensin NTS2 peptide– peptoid hybrids proline analogues structure– activity relationships |
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