Structure-Based Evolution of Subtype-Selective Neurotensin Receptor Ligands

Schaab C, Kling R, Einsiedel J, Hübner H, Clark T, Seebach D, Gmeiner P (2014)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2014

Journal

ChemistryOpen Wiley Open Access: Chemistry Open / Wiley

Publisher: Wiley Open Access: Chemistry Open / Wiley

Book Volume: 3

Pages Range: 206-218

DOI: 10.1002/open.201402031

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 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.

Authors with CRIS profile

Carolin Schaab Lehrstuhl für Pharmazeutische Chemie Ralf Kling Lehrstuhl für Pharmazeutische Chemie Jürgen Einsiedel Lehrstuhl für Pharmazeutische Chemie Harald Hübner Lehrstuhl für Pharmazeutische Chemie Timothy Clark Computer-Chemie-Centrum Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Additional Organisation(s)

Emil-Fischer-Zentrum (Emil Fischer Center)

Involved external institutions

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

How to cite

APA:

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. https://dx.doi.org/10.1002/open.201402031

MLA:

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

BibTeX: Download