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

Molecules

Agata Siwek¹  Marek Bednarski²  Kinga Czarnota³  Jadwiga Handzlik³  Sabina Podlewska³  Katarzyna Kieć-Kononowicz³  Katarzyna Kucwaj-Brysz³  Anna Dela³  Grzegorz Satała⁴ 

[1] Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Street, 30-688 Kraków, Poland;Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Street, 30-688 Kraków, Poland;Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland;Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland;

关键词: adrenergic receptors;    serotonin receptors;    G protein-coupled receptors;    selectivity;    docking;    molecular dynamics;   

DOI  :  10.3390/molecules26227025

来源: DOAJ

【 摘 要 】

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 α_1A/α_1D affinity and selectivity towards α_1B, 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.

【 授权许可】

Unknown