The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives.

Katarzyna Kucwaj-Brysz,Sabina Podlewska,Katarzyna Kieć-Kononowicz,Jadwiga Handzlik,Grzegorz Satała,Agata Siwek,Kinga Czarnota,Anna Dela,Marek Bednarski

doi:10.3390/molecules26227025

Abstract

Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α1A/α1D affinity and selectivity towards α1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents.

Highlights

The α1 -adrenergic receptors (ARs) belong to the great G-protein coupled receptor’s (GPCR’s) family and their role is the mediation of the sympathetic nervous system via binding endogenous catecholamines [1]
Thanks to the ability to relax the smooth muscle in the prostate, the α1 -AR blockers found mainly clinical use in the treatment of benign prostatic hyperplasia (BPH)—the enlargement of the prostate gland, which may further lead to lower urinary tract symptoms (LUTS), significantly decreasing quality of life [3]
Potential application of α1 -AR blockers was indicated as an efficient treatment in cocaine use disorder (CUD)

Summary

Introduction

The α1 -adrenergic receptors (ARs) belong to the great G-protein coupled receptor’s (GPCR’s) family and their role is the mediation of the sympathetic nervous system via binding endogenous catecholamines (adrenaline and noradrenaline) [1]. The deep characterization of tissue in the 1980s led to a division of ARs into three subtypes: α1A -AR, α1B -AR and α1D -AR [2]. Thanks to the ability to relax the smooth muscle in the prostate, the α1 -AR blockers found mainly clinical use in the treatment of benign prostatic hyperplasia (BPH)—the enlargement of the prostate gland, which may further lead to lower urinary tract symptoms (LUTS), significantly decreasing quality of life [3]. The common side effect concerns hypotension, which is most probably due to the result of interactions with the subtype α1B -AR. Potential application of α1 -AR blockers was indicated as an efficient treatment in cocaine use disorder (CUD) For the tamsulosin—the selective α1A /α1D -AR antagonist (affinity to α1A/ α1D is 10-fold stronger than to α1B )—a significantly less undesired cardiovascular α1A/α1D is 10-fold stronger than to α1B)—a significantly less undesired cardiovascular extension effect was extension effect wasobserved observedthan thanfor forthe the non-subtype non-subtype selective selective α11-AR

Methods

Discussion

Conclusion