Compound 11g(Pontifical Catholic University of Rio de Janeiro)

Anxiety and other neurotic disorders are significant medical and social issues, affecting 10-20% of people in developed countries, with an annual increase of over 10%. These conditions are becoming a greater concern due to treatment costs, missed work, decreased productivity, and their impact on relationships and socialization. As a result, developing effective treatments for neurotic disorders is a key goal in medicine and pharmacology. For the first time, we synthesized derivatives containing both tryptamine and triazine fragments and demonstrated their neurotropic activity, in particular their anxiolytic effect. When examining their binding using the docking method (Autodock Vina multiligand) to the GABAa receptor (PDB ID: 6X3X) and GABA-AT (PDB ID: 1SF2), compounds 4-11a-i showed minimal binding energies. In animal studies, compounds 9b and 11g demonstrated notable antianxiety effects, influencing behaviors such as approach to the arena center, grooming, and bolus count. Compound 11g 6-(4-chlorobenzyl)-3-[2-(6-methoxy-1H-indol-3-yl)-ethylamino]-4H-[1,2,4]triazin-5-one had the lowest IC₅₀ value at 19.8 ± 0.62, indicating high potency, and appeared to function similarly to diazepam without impairing normal exploration or movement. Notably, 9b outperformed other tested drugs. Its derivative 11g displayed the lowest energy binding with GABA_A receptor and GABA-AT, which likely accounts for its high activity.