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

Toni Kühl; Maya G Georgieva; Harald Hübner; Maria Lazarova; Matthias Vogel; Bodo Haas; Martina I Peeva; Aneliya A Balacheva; Ivan P Bogdanov; Luigi Milella; Maria Ponticelli; Tsvetomir Garev; Immacolata Faraone; Roumyana Detcheva; Borislav Minchev; Polina Petkova-Kirova; Lyubka Tancheva; Reni Kalfin; Atanas G Atanasov; Liudmil Antonov; Tamara I Pajpanova; Kiril Kirilov; Marcus Gastreich; Peter Gmeiner; Diana Imhof; Nikolay T Tzvetkov

doi:10.1016/j.ejmech.2023.115386

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

Eur J Med Chem. 2023 Jun 5:254:115386. doi: 10.1016/j.ejmech.2023.115386. Epub 2023 Apr 17.

Authors

Toni Kühl¹, Maya G Georgieva², Harald Hübner³, Maria Lazarova⁴, Matthias Vogel⁵, Bodo Haas⁵, Martina I Peeva², Aneliya A Balacheva², Ivan P Bogdanov², Luigi Milella⁶, Maria Ponticelli⁶, Tsvetomir Garev⁷, Immacolata Faraone⁸, Roumyana Detcheva², Borislav Minchev⁴, Polina Petkova-Kirova⁴, Lyubka Tancheva⁹, Reni Kalfin⁴, Atanas G Atanasov¹⁰, Liudmil Antonov¹¹, Tamara I Pajpanova², Kiril Kirilov¹², Marcus Gastreich¹³, Peter Gmeiner³, Diana Imhof¹, Nikolay T Tzvetkov¹⁴

Affiliations

¹ Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany.
² Department of Biochemical Pharmacology and Drug Design, Institute of Molecular Biology "Roumen Tsanev", Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 21, Sofia, 1113, Bulgaria.
³ Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander- Universität Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, D-91058, Erlangen, Germany.
⁴ Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 23, 1113, Sofia, Bulgaria.
⁵ Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Germany.
⁶ Department of Science, University of Basilicata, V.le dell'Ateneo Lucano 10, 85100, Potenza, Italy.
⁷ UMBALSM "N. I. Pirogov"-Hospital, 1606 Pette Kyosheta, Sofia, Bulgaria.
⁸ Department of Science, University of Basilicata, V.le dell'Ateneo Lucano 10, 85100, Potenza, Italy; Innovative Startup Farmis s.r.l., Via Nicola Vaccaro 40, 85100, Potenza, Italy.
⁹ Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 23, 1113, Sofia, Bulgaria; Weizmann Institute of Science, 234 Herzl St., Rehovot, 7610001, Israel.
¹⁰ Ludwig Boltzmann Institute for Digital Health and Patient Safety, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria; Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, 05-552, Magdalenka, Poland.
¹¹ Institute of Electronics, Bulgarian Academy of Sciences, Blvd. Tsarigradsko Chaussee 72, 1784, Sofia, Bulgaria.
¹² Department of Biochemical Pharmacology and Drug Design, Institute of Molecular Biology "Roumen Tsanev", Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 21, Sofia, 1113, Bulgaria; Department of Natural Sciences, New Bulgarian University, 21 Montevideo Str., Sofia, 1618, Bulgaria.
¹³ BioSolveIT GmbH, An der Ziegelei 79, 53757 St. Augustin, Germany.
¹⁴ Department of Biochemical Pharmacology and Drug Design, Institute of Molecular Biology "Roumen Tsanev", Bulgarian Academy of Sciences, Acad. G. Bonchev Str., bl. 21, Sofia, 1113, Bulgaria. Electronic address: ntzvetkov@bio21.bas.bg.

PMID: 37094450
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.

Keywords: Agonists; Neurotensin; Neurotensin receptors; Parkinson's disease; Peptide analogs.

MeSH terms

Animals
Dopamine
Humans
Ligands
Mice
Neurotensin* / metabolism
Neurotensin* / pharmacology
Parkinson Disease* / drug therapy
Protein Binding
Receptors, Neurotensin / metabolism

Substances

Dopamine
Ligands
Neurotensin
Receptors, Neurotensin
NTSR2 protein, human