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

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 signif-icantly increased the total motor activity of Balb/c mice compared to the control. The structure-activity relationship was investigated. The most effective compound was found to be GML-11 (N-benzyl-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.

Automated summary

New TSPO ligands with high anxiolytic activity in the series of N,1-diphenylpyrrolo[1,2-a]pyrazine-3-carboxamides were successfully designed using calculated pharmacophore model and molecular docking analysis.