Design, Synthesis, and Biological Evaluation of a Series of 5- and 7-Hydroxycoumarin Derivatives as 5-HT1A Serotonin Receptor Antagonists.

Kinga Ostrowska,Bartosz Trzaskowski,Jagoda Chmiel,Magdalena Bujalska-Zadrożny,Zuzanna Czarnocka,Anna Leśniak

doi:10.3390/ph14030179

Kinga Ostrowska, Bartosz Trzaskowski + Show 4 more

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https://doi.org/10.3390/ph14030179

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Abstract

We have designed and synthesized a series of 60 new 5- and 7-hydroxycoumarin derivatives bearing the piperazine moiety with the expected binding to 5-HT1A and 5-HT2A receptors. Molecular docking of all investigated compounds revealed subnanomolar estimates of 5-HT1AR Ki for three ligands and 5-HT2AR Ki for one ligand as well as numerous low nanomolar estimates of Ki for both receptors. Intrigued by these results we synthesized all 60 new derivatives using microwave-assisted protocols. We show that three new compounds show a relatively high antagonistic activity against the 5HT1A receptor, although lower than the reference compound WAY-100635. These compounds also showed relatively low binding affinities to the 5-HT2A receptor. We also provide a detailed structure–activity analysis of this series of compounds and compare it with previously obtained results for an exhaustive series of coumarin derivatives.

Highlights

N-arylpiperazine-containing ligands are a large class of chemical compounds with various known biological activities, such as enzyme inhibition, antibacterial, antineoplastic, and anticancer properties, as well as adrenergic and serotonin receptor inhibition [1,2,3,4,5,6,7]
Inspired by these works we have expanded the family of potential serotonin agonists/antagonists based on the same design principle by introducing different arylpiperazine derivatives of 7-hydroxycoumarin, some of which showed subnanomolar affinities to 5-HT1A receptor and low nanomolar affinities to 5-HT2A receptor [19,20]
We showed that the highest, subnanomolar affinities for 5-HT1A receptor were associated with the presence of the acetyl group in the C-6 position at the coumarin ring and the substituents in the 2 or 3 position in the phenyl ring of piperazine

Summary

Introduction

N-arylpiperazine-containing ligands are a large class of chemical compounds with various known biological activities, such as enzyme inhibition, antibacterial, antineoplastic, and anticancer properties, as well as adrenergic and serotonin receptor inhibition [1,2,3,4,5,6,7]. Among many groups considered as the bulky moiety connected to N-arylpiperazine coumarin derivatives have gained some attention, after the investigations of Chen et al, who showed that selected N-arylpiperazines connected to coumarins in position 7 via a (CH2 ) linker have nanomolar Ki values toward 5-HT1A and 5-HT2A receptors [17,18]. Inspired by these works we have expanded the family of potential serotonin agonists/antagonists based on the same design principle by introducing different arylpiperazine derivatives of 7-hydroxycoumarin, some of which showed subnanomolar affinities to 5-HT1A receptor and low nanomolar affinities to 5-HT2A receptor [19,20]. Later we have obtained a series of arylpiperazine derivatives of 5-hydroxycoumarin [21,22,23]

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