Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties
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<sub>2</sub>-adrenoceptor might be benefici...
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doaj-3d558fc453414e93aad47bd1aa904ce42021-07-15T15:42:04ZengMDPI AGMolecules1420-30492021-06-01263828382810.3390/molecules26133828Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like PropertiesVittorio Canale0Magdalena Kotańska1Anna Dziubina2Matylda Stefaniak3Agata Siwek4Gabriela Starowicz5Krzysztof Marciniec6Patryk Kasza7Grzegorz Satała8Beata Duszyńska9Xavier Bantreil10Frédéric Lamaty11Marek Bednarski12Jacek Sapa13Paweł Zajdel14Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandDepartment of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandDepartment of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandDepartment of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandDepartment of Organic Chemistry, Medical University of Silesia, 41-200 Sosnowiec, PolandDepartment of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandDepartment of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, PolandDepartment of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, PolandIBMM, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, FranceIBMM, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, FranceDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandDepartment of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandDepartment of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, PolandThe 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<sub>2</sub>-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<sub>7</sub> receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α<sub>2</sub>-adrenoceptors and 5-HT<sub>7</sub> 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 <b>8</b> behaved as a potent α<sub>2A</sub>/5-HT<sub>7</sub> receptor antagonist and displayed moderate-to-high selectivity over α<sub>1</sub>-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound <b>8</b> improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.https://www.mdpi.com/1420-3049/26/13/3828α<sub>2</sub> adrenoceptor antagonist5-HT<sub>7</sub> receptor antagonistmedicinal mechanochemistrydepressionforced swim test |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vittorio Canale Magdalena Kotańska Anna Dziubina Matylda Stefaniak Agata Siwek Gabriela Starowicz Krzysztof Marciniec Patryk Kasza Grzegorz Satała Beata Duszyńska Xavier Bantreil Frédéric Lamaty Marek Bednarski Jacek Sapa Paweł Zajdel |
spellingShingle |
Vittorio Canale Magdalena Kotańska Anna Dziubina Matylda Stefaniak Agata Siwek Gabriela Starowicz Krzysztof Marciniec Patryk Kasza Grzegorz Satała Beata Duszyńska Xavier Bantreil Frédéric Lamaty Marek Bednarski Jacek Sapa Paweł Zajdel Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties Molecules α<sub>2</sub> adrenoceptor antagonist 5-HT<sub>7</sub> receptor antagonist medicinal mechanochemistry depression forced swim test |
author_facet |
Vittorio Canale Magdalena Kotańska Anna Dziubina Matylda Stefaniak Agata Siwek Gabriela Starowicz Krzysztof Marciniec Patryk Kasza Grzegorz Satała Beata Duszyńska Xavier Bantreil Frédéric Lamaty Marek Bednarski Jacek Sapa Paweł Zajdel |
author_sort |
Vittorio Canale |
title |
Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties |
title_short |
Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties |
title_full |
Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties |
title_fullStr |
Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties |
title_full_unstemmed |
Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties |
title_sort |
design, sustainable synthesis and biological evaluation of a novel dual α2a/5-ht7 receptor antagonist with antidepressant-like properties |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2021-06-01 |
description |
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<sub>2</sub>-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<sub>7</sub> receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α<sub>2</sub>-adrenoceptors and 5-HT<sub>7</sub> 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 <b>8</b> behaved as a potent α<sub>2A</sub>/5-HT<sub>7</sub> receptor antagonist and displayed moderate-to-high selectivity over α<sub>1</sub>-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound <b>8</b> improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine. |
topic |
α<sub>2</sub> adrenoceptor antagonist 5-HT<sub>7</sub> receptor antagonist medicinal mechanochemistry depression forced swim test |
url |
https://www.mdpi.com/1420-3049/26/13/3828 |
work_keys_str_mv |
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