Structure-Based Evolution of Subtype-Selective Neurotensin Receptor Ligands

Journal article
(Original article)

Publication Details

Author(s): Schaab C, Kling R, Einsiedel J, Hübner H, Clark T, Seebach D, Gmeiner P
Journal: ChemistryOpen
Publisher: Wiley Open Access: Chemistry Open / Wiley
Publication year: 2014
Volume: 3
Pages range: 206-218
ISSN: 2191-1363
Language: English


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 m-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 β2-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 2a, [(S)-3-(pyrazolo[1,5-α]pyridine-5-yl)-propionyl11]NT(8-13), exhibits substantial NTS2 affinity (4.8 nm) and has a nearly 30-fold NTS2 selectivity over NTS1. The (R)-epimer 2b showed lower NTS2 affinity but more than 600-fold selectivity over NTS1.

FAU Authors / FAU Editors

Clark, Timothy apl. Prof. Dr.
Einsiedel, Jürgen Dr.
Lehrstuhl für Pharmazeutische Chemie
Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Kling, Ralf
Lehrstuhl für Pharmazeutische Chemie
Schaab, Carolin
Lehrstuhl für Pharmazeutische Chemie

Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)

External institutions with authors

Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich

How to cite

Schaab, C., Kling, R., Einsiedel, J., Hübner, H., Clark, T., Seebach, D., & Gmeiner, P. (2014). Structure-Based Evolution of Subtype-Selective Neurotensin Receptor Ligands. ChemistryOpen, 3, 206-218.

Schaab, Carolin, et al. "Structure-Based Evolution of Subtype-Selective Neurotensin Receptor Ligands." ChemistryOpen 3 (2014): 206-218.


Last updated on 2019-15-03 at 07:47