title: Impact of the proline residue on ligand binding of neurotensin receptor 2 (NTS2)-selective peptide-peptoid hybrids.
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 (19) F magnetic resonance imaging.
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Held
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Ralf
authors.initials: R
authors.lastname: Kling
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Nagel
authors.forename: Helma
authors.initials: H
authors.lastname: Wennemers
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D034444:Peptoids / Q000737:chemistry / Q000494:pharmacology*; D011392:Proline / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; C490985:NTSR2 protein, human; D010455:Peptides; D034444:Peptoids; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D011392:Proline