title: Structure-based evolution of subtype-selective neurotensin receptor ligands.
abstract: Subtype-selective agonists of the neurotensin receptor NTS2 represent a promising option for the treatment of neuropathic pain, as NTS2 is involved in the mediation of μ-opioid-independent anti-nociceptive effects. Based on the crystal structure of the subtype NTS1 and previous structure-activity relationships (SARs) indicating a potential role for the sub-pocket around Tyr11 of NT(8-13) in subtype-specific ligand recognition, we have developed new NTS2-selective ligands. Starting from NT(8-13), we replaced the tyrosine unit by β(2)-amino acids (type 1), by heterocyclic tyrosine bioisosteres (type 2) and peptoid analogues (type 3). We were able to evolve an asymmetric synthesis of a 5-substituted azaindolylalanine and its application as a bioisostere of tyrosine capable of enhancing NTS2 selectivity. The S-configured test compound 2 a, [(S)-3-(pyrazolo[1,5-a]pyridine-5-yl)-propionyl(11)]NT(8-13), exhibits substantial NTS2 affinity (4.8 nm) and has a nearly 30-fold NTS2 selectivity over NTS1. The (R)-epimer 2 b showed lower NTS2 affinity but more than 600-fold selectivity over NTS1.
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University Schuhstraße 19, 91052 Erlangen (Germany) E-mail: peter.gmeiner@fau.de.
authors.forename: Carolin
authors.initials: C
authors.lastname: Schaab
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University Schuhstraße 19, 91052 Erlangen (Germany) E-mail: peter.gmeiner@fau.de ; Department of Chemistry and Pharmacy, Computer Chemistry Center, Friedrich Alexander University Nägelsbachstraße 25, 91052 Erlangen (Germany).
authors.forename: Ralf Christian
authors.initials: RC
authors.lastname: Kling
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University Schuhstraße 19, 91052 Erlangen (Germany) E-mail: peter.gmeiner@fau.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Einsiedel
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University Schuhstraße 19, 91052 Erlangen (Germany) E-mail: peter.gmeiner@fau.de.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Chemistry and Pharmacy, Computer Chemistry Center, Friedrich Alexander University Nägelsbachstraße 25, 91052 Erlangen (Germany).
authors.forename: Tim
authors.initials: T
authors.lastname: Clark
authors.affiliation: Departement of Chemistry and Applied Bioscience, Laboratory of Organic Chemistry ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland).
authors.forename: Dieter
authors.initials: D
authors.lastname: Seebach
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University Schuhstraße 19, 91052 Erlangen (Germany) E-mail: peter.gmeiner@fau.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
keywords: NTS2; neurotensin; subtype selectivity; tyrosine analogues; β2-amino acids