title: Development of a metabolically stable neurotensin receptor 2 (NTS2) ligand.
abstract: Subtype-selective neurotensin receptor 2 (NTS2) ligands can be used as molecular probes to investigate the physiological role of neurotensinergic systems and serve as lead compounds to initiate the development of drugs for the treatment of tonic pain. Starting from our recently described NTS2 ligand 1, structural variants of type 2 were synthesized to further improve binding affinity and selectivity to gain metabolic stability. The peptide-peptoid hybrid 2 b showed excellent NTS2 binding affinity (K(i) =2.8 nM) and 22 000-fold selectivity over NTS1, as well as metabolic stability over 32 h in a serum degradation assay. Employing a MAPK-driven luciferase reporter gene assay and an IP accumulation assay, the neurotensin mimetic 2 b displayed respective inhibitions of constitutive activity exceeding 4.3- and 3.9-fold that of the inverse agonist activity of the endogenous ligand neurotensin.
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: Manuel
authors.initials: M
authors.lastname: Plomer
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Jasmin
authors.initials: J
authors.lastname: Meltretter
authors.forename: Monika
authors.initials: M
authors.lastname: Pischetsrieder
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D009496:Neurotensin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D034444:Peptoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018028:Receptors, Neurotensin / Q000378:metabolism*; D044967:Serum / Q000378:metabolism
chemical_list: D008024:Ligands; C490985:NTSR2 protein, human; D010455:Peptides; D034444:Peptoids; D018028:Receptors, Neurotensin; D009496:Neurotensin