title: NTS2-selective neurotensin mimetics with tetrahydrofuran amino acids.
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 Tyr11in NT(8-13). Additionally, Arg8, Arg9, and Ile12of 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.
authors.affiliation: Faculty of Chemistry and Pharmacy, Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
authors.forename: Nadja A
authors.initials: NA
authors.lastname: Simeth
authors.affiliation: Faculty of Chemistry and Pharmacy, Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Bause
authors.affiliation: Faculty of Chemistry and Pharmacy, Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Dobmeier
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen Nürnberg (FAU), Schuhstr. 19, 91052 Erlangen, Germany; Institute of Physiology, Paracelsus Medical University Nürnberg, 90419 Nürnberg, Germany.
authors.forename: Ralf C
authors.initials: RC
authors.lastname: Kling
authors.affiliation: Faculty of Chemistry and Pharmacy, Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lachmann
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen Nürnberg (FAU), Schuhstr. 19, 91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen Nürnberg (FAU), Schuhstr. 19, 91052 Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Einsiedel
authors.affiliation: Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen Nürnberg (FAU), Schuhstr. 19, 91052 Erlangen, Germany. Electronic address: peter.gmeiner@fau.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Faculty of Chemistry and Pharmacy, Institute of Organic Chemistry, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany. Electronic address: burkhard.koenig@ur.de.
authors.forename: Burkhard
authors.initials: B
authors.lastname: König
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D003412:Cricetulus; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D018716:Molecular Mimicry; D009496:Neurotensin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018028:Receptors, Neurotensin / Q000819:agonists*
chemical_list: D005663:Furans; C490985:NTSR2 protein, human; D010446:Peptide Fragments; D057786:Peptidomimetics; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; C041968:neurotensin (1-8); D011761:Pyrrolidonecarboxylic Acid
keywords: Neurotensin; Non-natural amino acid; Peptides