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

被引：6

作者：

Kuehl, Toni ^{[1
]}

Georgieva, Maya G. ^{[2
]}

Huebner, Harald ^{[3
]}

Lazarova, Maria ^{[4
]}

Vogel, Matthias ^{[5
]}

Haas, Bodo ^{[4
,5
]}

Peeva, Martina I. ^{[2
]}

Balacheva, Aneliya A. ^{[2
]}

Bogdanov, Ivan P. ^{[2
]}

Milella, Luigi ^{[6
]}

Ponticelli, Maria ^{[6
]}

Garev, Tsvetomir ^{[7
]}

Faraone, Immacolata ^{[6
,8
]}

Detcheva, Roumyana ^{[2
]}

Minchev, Borislav ^{[4
]}

Petkova-Kirova, Polina ^{[4
]}

Tancheva, Lyubka ^{[4
,9
]}

Kalfin, Reni ^{[4
]}

Atanasov, Atanas G. ^{[10
]}

Antonov, Liudmil

Pajpanova, Tamara I.

Kirilov, Kiril ^{[2
]}

Gastreich, Marcus

Gmeiner, Peter ^{[3
]}

Imhof, Diana ^{[1
]}

Tzvetkov, Nikolay T. ^{[2
]}

机构：

[1] Univ Bonn, Pharmaceut Inst, Pharmaceut Biochem & Bioanalyt, Immenburg 4, D-53121 Bonn, Germany

[2] Bulgarian Acad Sci, Inst Mol Biol Roumen Tsanev, Dept Biochem Pharmacol & Drug Design, Acad G Bonchev Str,Bl 21, Sofia 1113, Bulgaria

[3] Friedrich Alexander Univ Erlangen Nurnberg, Dept Chem & Pharm, Med Chem, Nikolaus Fiebiger Str 10, D-91058 Erlangen, Germany

[4] Bulgarian Acad Sci, Inst Neurobiol, Acad G Bonchev Str,Bl 23, Sofia 1113, Bulgaria

[5] Fed Inst Drugs & Med Devices BfArM, Kurt Georg Kiesinger Allee 3, D-53175 Bonn, Germany

[6] Univ Basilicata, Dept Sci, Vle Ateneo Lucano 10, I-85100 Potenza, Italy

[7] UMBALSM NI Pirogov Hosp, Sofia 1606, Bulgaria

[8] Innovat Startup Farmis Srl, Via Nicola Vaccaro 40, I-85100 Potenza, Italy

[9] Weizmann Inst Sci, 234 Herzl St, IL-7610001 Rehovot, Israel

[10] Med Univ Vienna, Ludwig Boltzmann Inst Digital Hlth & Patient Safet, Spitalgasse 23, A-1090 Vienna, Austria

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 254卷

关键词：

Neurotensin; Peptide analogs; Agonists; Neurotensin receptors; Parkinson 's disease; MONOAMINE-OXIDASE B; FUNCTIONAL-CHARACTERIZATION; ARTIFICIAL MEMBRANE; BINDING; DOPAMINE; DESIGN; DERIVATIVES; IMPLEMENTATION; IDENTIFICATION; SUBNANOMOLAR;

D O I：

10.1016/j.ejmech.2023.115386

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页数：15

共 44 条

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