Novel 5-HT 7 R antagonists, arylsulfonamide derivatives of (aryloxy)propyl piperidines: Add-on effect to the antidepressant activity of SSRI and DRI, and pro-cognitive profile

Canale, Vittorio; Partyka, Anna; Kurczab, Rafał; Krawczyk, Martyna; Kos, Tomasz; Satała, Grzegorz; Kubica, Bartłomiej; Jastrzębska-Więsek, Magdalena; Wesołowska, Anna; Bojarski, Andrzej J.; Popik, Piotr; Zajdel, Paweł

doi:10.1016/j.bmc.2017.03.057

Cited by 20 publications

(21 citation statements)

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“…To complete the examination of the conformational preferences of the studied compounds, molecular docking of azinesulfonamides was performed with the use of recently developed 5-HT 7 and 5-HT 1A homology models, built on a dopaminergic D 3 receptor template (PDB ID: 3PBL) [ 13 , 26 – 31 ]. Next, the combination of the QPLD with MM-generalized-born/surface area (MM/GBSA) calculations from the Schrödinger Suite was used to obtain ligand–receptor complexes, as this approach is suitable to describe the anisotropy of the electron density of halogen atoms, which is a key feature during halogen bond examination [ 32 ].…”

Section: Resultsmentioning

confidence: 99%

Structural determinants influencing halogen bonding: a case study on azinesulfonamide analogs of aripiprazole as 5-HT1A, 5-HT7, and D2 receptor ligands

Marciniec

Kurczab

Książek

et al. 2018

Chemistry Central Journal

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A series of azinesulfonamide derivatives of long-chain arylpiperazines with variable-length alkylene spacers between sulfonamide and 4-arylpiperazine moiety is designed, synthesized, and biologically evaluated. In vitro methods are used to determine their affinity for serotonin 5-HT1A, 5-HT6, 5-HT7, and dopamine D2 receptors. X-ray analysis, two-dimensional NMR conformational studies, and docking into the 5-HT1A and 5-HT7 receptor models are then conducted to investigate the conformational preferences of selected serotonin receptor ligands in different environments. The bent conformation of tetramethylene derivatives is found in a solid state, in dimethyl sulfoxide, and as a global energy minimum during conformational analysis in a simulated water environment. Furthermore, ligand geometry in top-scored complexes is also bent, with one torsion angle in the spacer (τ2) in synclinal conformation. Molecular docking studies indicate the role of halogen bonding in complexes of the most potent ligands and target receptors. Electronic supplementary materialThe online version of this article (10.1186/s13065-018-0422-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Structural determinants influencing halogen bonding: a case study on azinesulfonamide analogs of aripiprazole as 5-HT1A, 5-HT7, and D2 receptor ligands

Marciniec

Kurczab

Książek

et al. 2018

Chemistry Central Journal

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“…[ 118 ] In a subsequent article, Zajdel and co‐workers further designed and synthesized a novel series of arylsulfonamide derivatives based on PZ‐766 and PZ‐1404. [ 119 ] The SARs studies indicated that the elongation between 2 and 3 methylene units maintained a high affinity for the 5‐HT 7 receptor and selectivity over the 5‐HT 1A receptor. Among all the screened compounds, compound 48 (Figure 9) produced positive antidepressant effects in the FST and TST (MED = 0.625 and 1.25 mg kg −1 , respectively, i.p.…”

Section: Advances In Small Molecules With Antidepressant Activitiesmentioning

confidence: 99%

Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules

Yao

Jiang

et al. 2022

Advanced Therapeutics

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Depression is one of the most prevalent mental diseases and a primary cause of disability worldwide with high incidence and high recurrence. The current deterioration of the COVID‐19 epidemic also pushes up the incidence of depression. Nevertheless, the currently available treatments remain inadequate response and limited efficacy. Therefore, discoveries of more potent and safer antidepressant drugs are urgently needed. In this review, the current potential physiological and pathological mechanisms of depression, and the clinical research progresses of candidate drugs as well as the recent advances in small‐molecule drug discovery for potential treatments of depression are systematically summarized. More importantly, the structure–activity relationships of compounds from different classes, the statistical analysis of the blood‐brain barrier permeability, the pharmacological targets, and the in vivo models are comprehensively discussed. Further insights on antidepressant drug discovery are also analyzed from multidimensional perspectives.

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“…Mp for C 18 H 28 N 2 O 2 HCl: 110.9-112.4 • C.3.1.5. Sulfonylation of Primary Amine (Procedure D) for the Preparation of Final Compounds(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)…”

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confidence: 99%

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

et al. 2021

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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 α2-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 α2-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 α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-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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Novel 5-HT 7 R antagonists, arylsulfonamide derivatives of (aryloxy)propyl piperidines: Add-on effect to the antidepressant activity of SSRI and DRI, and pro-cognitive profile

Cited by 20 publications

References 35 publications

Structural determinants influencing halogen bonding: a case study on azinesulfonamide analogs of aripiprazole as 5-HT1A, 5-HT7, and D2 receptor ligands

Structural determinants influencing halogen bonding: a case study on azinesulfonamide analogs of aripiprazole as 5-HT1A, 5-HT7, and D2 receptor ligands

Antidepressant Drug Discovery and Development: Mechanism and Drug Design Based on Small Molecules

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

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