期刊
MOLECULES
卷 26, 期 13, 页码 -出版社
MDPI
DOI: 10.3390/molecules26133828
关键词
alpha(2) adrenoceptor antagonist; 5-HT7 receptor antagonist; medicinal mechanochemistry; depression; forced swim test
资金
- Ministere de l'Europe et des Affaires Etrangeres and Polish Minister of Science and Higher Education (PHC Polonium program)
- National Science Center, Poland [2011/03/B/NZ7/00635, 2019/33/B/NZ7/02822]
The study designed and synthesized a series of dual-acting ligands arylsulfonamide derivatives of dihydrobenzofuranoxy)ethyl piperidines, with compound 8 showing potential for treating depressive symptoms and high selectivity. By targeting both alpha(2)-adrenoceptors and 5-HT7 receptors, these compounds could be potential candidates for future antidepressants.
The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of alpha(2)-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both alpha(2)-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent alpha(2A)/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over alpha(1)-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.
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