Design, Synthesis, and Study of Anxiolytic Activity of New Pyrrolo[1,2-a]Pyrazine-Containing TSPO Ligands

-A new group of 1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamides, with alkyl, benzyl or alkoxyphenylalkyl groups, amino acid residues or their derivatives as substituents at the amide nitrogen atom, was obtained. The synthesized compounds have high theoretical affinity values to the 18-kDa translocator protein (TSPO) and a favorable profile of ADMET characteristics, which determines their prospects for development as medicines. An anxiolytic activity was detected in eight compounds at doses of 0.1-5.0 mg/kg with intraperitoneal administration under conditions of emotional stress in the open field test in Balb/c line mice and in the elevated plus maze test in ICR mice. A leader compound N-benzhydryl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxyamide, which demonstrated the presence of antianxiety activity in a wide range of doses in both tests, was selected as a potential anxiolytic agent for subsequent development.

Automated summary

A new group of 1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamides was synthesized with various substituents at the amide nitrogen, such as alkyl, benzyl or alkoxyphenylalkyl groups, amino acid residues or their derivatives. These compounds exhibited high theoretical affinity values to the 18-kDa translocator protein (TSPO) and showed favorable pharmacokinetic properties, indicating their potential as drugs. Several compounds demonstrated anxiolytic activity in mice under emotional stress conditions, and a lead compound N-benzhydryl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxyamide was selected for further development as a potential anxiolytic agent.