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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Design, Synthesis and Pharmacological Activity of New Pyrrolo[1,2-A] Pyrazine Translocator Protein (TSPO) Ligands

Author(s): Grigory Mokrov*, Andry Pantileev, Milada Yarkova, Tatiana Gudasheva and Sergei Seredenin

Volume 18, Issue 4, 2022

Published on: 06 August, 2021

Page: [497 - 508] Pages: 12

DOI: 10.2174/1573406417666210806095051

Price: $65

Abstract

Background: Translocator protein 18 kDa (TSPO) is a promising target for the creation of effective and safe neuropsychotropic drugs. The ligands of TSPO exhibit anxiolytic, antidepressant, neuroprotective and other activities without the side effects of benzodiazepines.

Methods: New TSPO ligands in the series of N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides derivatives were designed using calculated pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out by two schemes using [3+3]-cycloaddition reaction of 2-azidoacrylic acid derivatives with pyrrolphenylketone as a key stage. The anxiolytic activity of new substances has been established using open field test with flash.

Results: Several synthesized N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides derivatives significantly increased the total motor activity of Balb/c mice compared to the control. The structureactivity relationship was investigated. The most effective compound was found to be GML-11 (Nbenzyl- N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamide), which had anxiolytic action in the dose range from 0.001 to 0.100 mg/kg (Balb/c, i.p.). This compound is two orders of magnitude higher in dose activity than all other pyrrolo[1,2-a]pyrazine TSPO ligands.

Conclusion: Molecular modelling methods allowed us to create new TSPO ligands in the series of N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides with high anxiolytic activity.

Keywords: Pyrrolo[1, 2-a]pyrazines, anxiolytic activity, TSPO ligands, open field test, 18 kDa translocator protein (TSPO), mice.

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