The New Dipeptide TSPO Ligands: Design, Synthesis and Structure–Anxiolytic Activity Relationship
The translocator protein (TSPO, 18 kDa) plays an important role in the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Stimulation of TSPO by appropriate ligands increase...
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MDPI AG
2020-11-01
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| Series: | Molecules |
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| author | Tatiana A. Gudasheva Olga A. Deeva Andrey S. Pantileev Grigory V. Mokrov Inna V. Rybina Milada A. Yarkova Sergei B. Seredenin |
| author_facet | Tatiana A. Gudasheva Olga A. Deeva Andrey S. Pantileev Grigory V. Mokrov Inna V. Rybina Milada A. Yarkova Sergei B. Seredenin |
| author_sort | Tatiana A. Gudasheva |
| collection | DOAJ |
| description | The translocator protein (TSPO, 18 kDa) plays an important role in the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Stimulation of TSPO by appropriate ligands increases the level of neurosteroids. The present study describes the design, synthesis and investigation of anxiolytic-like effects of a series of <i>N</i>-acyl-tryptophanyl-containing dipeptides. These novel dipeptide TSPO ligands were designed with the original drug-based peptide design strategy using alpidem as non-peptide prototype. The anxiolytic activities were investigated in Balb/C mice using the illuminated open-field and elevated plus-maze tests in outbred laboratory mice ICR (CD-1). Dipeptide GD-102 (<i>N</i>-phenylpropionyl-<span style="font-variant: small-caps;">l</span>-tryptophanyl-<span style="font-variant: small-caps;">l</span>-leucine amide) in the dose range of 0.01–0.5 mg/kg intraperitoneally (i.p.) has a pronounced anxiolytic activity. The anxiolytic effect of GD-102 was abolished by PK11195, a specific TSPO antagonist. The structure–activity relationship study made it possible to identify a pharmacophore fragment for the dipeptide TSPO ligand. It was shown that <span style="font-variant: small-caps;">l</span>,<span style="font-variant: small-caps;">d</span>-diastereomer of GD-102 has no activity, and the <span style="font-variant: small-caps;">d</span>,<span style="font-variant: small-caps;">l</span>-isomer has less pronounced activity. The anxiolytic activity also disappears by replacing the C-amide group with the methyl ester, a free carboxyl group or methylamide. Consecutive replacement of each amino acid residue with glycine showed the importance of each of the amino acid residues in the structure of the ligand. The most active and technologically available compound GD-102, was selected for evaluation as a potential anxiolytic drug. |
| first_indexed | 2024-03-10T15:05:43Z |
| format | Article |
| id | doaj.art-07f96a4d06ab4b1eb8a978eeab5971ba |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T15:05:43Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-07f96a4d06ab4b1eb8a978eeab5971ba2023-11-20T19:47:40ZengMDPI AGMolecules1420-30492020-11-012521513210.3390/molecules25215132The New Dipeptide TSPO Ligands: Design, Synthesis and Structure–Anxiolytic Activity RelationshipTatiana A. Gudasheva0Olga A. Deeva1Andrey S. Pantileev2Grigory V. Mokrov3Inna V. Rybina4Milada A. Yarkova5Sergei B. Seredenin6Federal State Budgetary Institution “Zakusov Research Institute of Pharmacology” (FSBI “Zakusov Institute of Pharmacology”), Baltiyskaya, 8, 125315 Moscow, RussiaFederal State Budgetary Institution “Zakusov Research Institute of Pharmacology” (FSBI “Zakusov Institute of Pharmacology”), Baltiyskaya, 8, 125315 Moscow, RussiaFederal State Budgetary Institution “Zakusov Research Institute of Pharmacology” (FSBI “Zakusov Institute of Pharmacology”), Baltiyskaya, 8, 125315 Moscow, RussiaFederal State Budgetary Institution “Zakusov Research Institute of Pharmacology” (FSBI “Zakusov Institute of Pharmacology”), Baltiyskaya, 8, 125315 Moscow, RussiaFederal State Budgetary Institution “Zakusov Research Institute of Pharmacology” (FSBI “Zakusov Institute of Pharmacology”), Baltiyskaya, 8, 125315 Moscow, RussiaFederal State Budgetary Institution “Zakusov Research Institute of Pharmacology” (FSBI “Zakusov Institute of Pharmacology”), Baltiyskaya, 8, 125315 Moscow, RussiaFederal State Budgetary Institution “Zakusov Research Institute of Pharmacology” (FSBI “Zakusov Institute of Pharmacology”), Baltiyskaya, 8, 125315 Moscow, RussiaThe translocator protein (TSPO, 18 kDa) plays an important role in the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Stimulation of TSPO by appropriate ligands increases the level of neurosteroids. The present study describes the design, synthesis and investigation of anxiolytic-like effects of a series of <i>N</i>-acyl-tryptophanyl-containing dipeptides. These novel dipeptide TSPO ligands were designed with the original drug-based peptide design strategy using alpidem as non-peptide prototype. The anxiolytic activities were investigated in Balb/C mice using the illuminated open-field and elevated plus-maze tests in outbred laboratory mice ICR (CD-1). Dipeptide GD-102 (<i>N</i>-phenylpropionyl-<span style="font-variant: small-caps;">l</span>-tryptophanyl-<span style="font-variant: small-caps;">l</span>-leucine amide) in the dose range of 0.01–0.5 mg/kg intraperitoneally (i.p.) has a pronounced anxiolytic activity. The anxiolytic effect of GD-102 was abolished by PK11195, a specific TSPO antagonist. The structure–activity relationship study made it possible to identify a pharmacophore fragment for the dipeptide TSPO ligand. It was shown that <span style="font-variant: small-caps;">l</span>,<span style="font-variant: small-caps;">d</span>-diastereomer of GD-102 has no activity, and the <span style="font-variant: small-caps;">d</span>,<span style="font-variant: small-caps;">l</span>-isomer has less pronounced activity. The anxiolytic activity also disappears by replacing the C-amide group with the methyl ester, a free carboxyl group or methylamide. Consecutive replacement of each amino acid residue with glycine showed the importance of each of the amino acid residues in the structure of the ligand. The most active and technologically available compound GD-102, was selected for evaluation as a potential anxiolytic drug.https://www.mdpi.com/1420-3049/25/21/5132TSPO ligandsdipeptidesGD-102molecular dockinganxiolytic activityelevated plus maze test |
| spellingShingle | Tatiana A. Gudasheva Olga A. Deeva Andrey S. Pantileev Grigory V. Mokrov Inna V. Rybina Milada A. Yarkova Sergei B. Seredenin The New Dipeptide TSPO Ligands: Design, Synthesis and Structure–Anxiolytic Activity Relationship Molecules TSPO ligands dipeptides GD-102 molecular docking anxiolytic activity elevated plus maze test |
| title | The New Dipeptide TSPO Ligands: Design, Synthesis and Structure–Anxiolytic Activity Relationship |
| title_full | The New Dipeptide TSPO Ligands: Design, Synthesis and Structure–Anxiolytic Activity Relationship |
| title_fullStr | The New Dipeptide TSPO Ligands: Design, Synthesis and Structure–Anxiolytic Activity Relationship |
| title_full_unstemmed | The New Dipeptide TSPO Ligands: Design, Synthesis and Structure–Anxiolytic Activity Relationship |
| title_short | The New Dipeptide TSPO Ligands: Design, Synthesis and Structure–Anxiolytic Activity Relationship |
| title_sort | new dipeptide tspo ligands design synthesis and structure anxiolytic activity relationship |
| topic | TSPO ligands dipeptides GD-102 molecular docking anxiolytic activity elevated plus maze test |
| url | https://www.mdpi.com/1420-3049/25/21/5132 |
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