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Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)‐Selective Peptide–Peptoid Hybrids
Author(s) -
Held Cornelia,
Hübner Harald,
Kling Ralf,
Nagel Yvonne A.,
Wennemers Helma,
Gmeiner Peter
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300054
Subject(s) - neurotensin , chemistry , peptide , neurotensin receptor , ligand (biochemistry) , residue (chemistry) , stereochemistry , receptor , peptoid , proline , biochemistry , amino acid , neuropeptide
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 ( K i =8.1–16 n M ) 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 19 F magnetic resonance imaging.