Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties.

Autor: Canale V; Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland., Kotańska M; Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland., Dziubina A; Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland., Stefaniak M; Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland., Siwek A; Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland., Starowicz G; Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland., Marciniec K; Department of Organic Chemistry, Medical University of Silesia, 41-200 Sosnowiec, Poland., Kasza P; Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland., Satała G; Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland., Duszyńska B; Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland., Bantreil X; IBMM, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, France., Lamaty F; IBMM, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, France., Bednarski M; Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland., Sapa J; Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland., Zajdel P; Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2021 Jun 23; Vol. 26 (13). Date of Electronic Publication: 2021 Jun 23.
DOI: 10.3390/molecules26133828
Abstrakt: 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 α 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-HT 7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α 2 -adrenoceptors and 5-HT 7 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 α 2A /5-HT 7 receptor antagonist and displayed moderate-to-high selectivity over α 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.
Databáze: MEDLINE
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