Neurotensin(8–13) analogs as dual NTS1 and NTS2 receptor ligands with enhanced effects on a mouse model of Parkinson's disease

Kühl T, Georgieva MG, Hübner H, Lazarova M, Vogel M, Haas B, Peeva MI, Balacheva AA, Bogdanov IP, Milella L, Ponticelli M, Garev T, Faraone I, Detcheva R, Minchev B, Petkova-Kirova P, Tancheva L, Kalfin R, Atanasov AG, Antonov L, Pajpanova TI, Kirilov K, Gastreich M, Gmeiner P, Imhof D, Tzvetkov NT (2023)

Publication Type: Journal article

Publication year: 2023

Journal

European Journal of Medicinal Chemistry Elsevier

Book Volume: 254

Article Number: 115386

DOI: 10.1016/j.ejmech.2023.115386

Abstract

The modulatory interactions between neurotensin (NT) and the dopaminergic neurotransmitter system in the brain suggest that NT may be associated with the progression of Parkinson's disease (PD). NT exerts its neurophysiological effects by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2). Therefore, both receptor subtypes are promising targets for the development of novel NT-based analogs for the treatment of PD. In this study, we used a virtually guided molecular modeling approach to predict the activity of NT(8–13) analogs by investigating the docking models of ligands designed for binding to the human NTS1 and NTS2 receptors. The importance of the residues at positions 8 and/or 9 for hNTS1 and hNTS2 receptor binding affinity was experimentally confirmed by radioligand binding assays. Further in vitro ADME profiling and in vivo studies revealed that, compared to the parent peptide NT(8–13), compound 10 exhibited improved stability and BBB permeability combined with a significant enhancement of the motor function and memory in a mouse model of PD. The herein reported NTS1/NTS2 dual-specific NT(8–13) analogs represent an attractive tool for the development of therapeutic strategies against PD and potentially other CNS disorders.

Authors with CRIS profile

Harald Hübner Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

Bulgarian Academy of Sciences (BAS) / Българска академия на науките BG Bulgaria (BG) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Institute of Molecular Biology (IMB) / Institute of Molecular Biology Roumen Tsanev / Институт по молекулярна биология BG Bulgaria (BG) National Institute of Emergency Medicine "Pirogov" / University Multiprofile Hospital for Active Treatment and Emergency Medicine BG Bulgaria (BG) BioSolveIT GmbH DE Germany (DE) Università degli Studi della Basilicata IT Italy (IT) Institute of Electronics “Academician Emil Djakov” (BAS IE) / Институт по електроника "Академик Емил Джаков" BG Bulgaria (BG) Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) / Federal Institute for Drugs and Medical Devices DE Germany (DE) Medizinische Universität Wien AT Austria (AT)

How to cite

APA:

Kühl, T., Georgieva, M.G., Hübner, H., Lazarova, M., Vogel, M., Haas, B.,... Tzvetkov, N.T. (2023). Neurotensin(8–13) analogs as dual NTS1 and NTS2 receptor ligands with enhanced effects on a mouse model of Parkinson's disease. European Journal of Medicinal Chemistry, 254. https://doi.org/10.1016/j.ejmech.2023.115386

MLA:

Kühl, Toni, et al. "Neurotensin(8–13) analogs as dual NTS1 and NTS2 receptor ligands with enhanced effects on a mouse model of Parkinson's disease." European Journal of Medicinal Chemistry 254 (2023).

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