BMY 7378, a selective α1D-adrenoceptor antagonist, is a new angiotensin converting enzyme inhibitor: In silico, in vitro and in vivo approach

IF 2.8 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jessica E. Rodríguez , Erik Andrade-Jorge , Alina Barquet-Nieto , Samuel E. Estrada-Soto , Itzell A. Gallardo-Ortíz , Rafael Villalobos-Molina
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Abstract

BMY 7378 is a multitarget drug primarily known for its selective antagonism of α1D-adrenoceptors (α1D-AR), exhibiting both hypotensive effects and the ability to prevent or reverse angiotensin II-induced vascular hypertrophy. Notably, BMY 7378 contains a phenylpiperazine moiety, a structural feature associated with angiotensin-converting enzyme (ACE) inhibition. This study aimed to investigate ACE inhibition as a potential pharmacological mechanism of BMY 7378. Using an in silico approach we predicted BMY 7378 interactions with the ACE active site, followed by in vitro activity assays. Additionally, ACE protein expression in the heart was analyzed following four weeks of BMY 7378 treatment in 7–8-month-old spontaneously hypertensive rats (SHR). All assays were benchmarked against captopril, a standard ACE inhibitor. In silico results showed that BMY 7378 binds to the ACE active site, though with reduced interaction with Zn701 (73.7 % compared to captopril), likely due to the pKa of its amino group. The inhibitory concentration 50 (IC50) for BMY 7378 was 136 μM, lower than other reported phenylpiperazine derivatives. Furthermore, BMY 7378 significantly increased ACE expression in the hearts of SHR, with an increase of 8.5-fold compared to captopril. In conclusion, BMY 7378 exhibits dual activity as an α1D-AR antagonist and an ACE inhibitor, making it a promising pharmacological tool for investigating and potentially treating hypertension and its associated cardiovascular complications.
BMY 7378是一种选择性α 1d肾上腺素能受体拮抗剂,是一种新型的血管紧张素转换酶抑制剂:硅、体外和体内方法。
BMY 7378是一种多靶点药物,主要以其α 1d -肾上腺素受体(α1D-AR)的选择性拮抗作用而闻名,具有降压作用和预防或逆转血管紧张素ii诱导的血管肥大的能力。值得注意的是,bmy7378含有苯哌嗪片段,这是一种与血管紧张素转换酶(ACE)抑制相关的结构特征。本研究旨在探讨bmy7378抑制ACE的潜在药理机制。利用计算机方法,我们预测了BMY 7378与ACE活性位点的相互作用,然后进行了体外活性测定。此外,在7-8月龄自发性高血压大鼠(SHR)接受BMY 7378治疗4周后,分析心脏中ACE蛋白的表达。所有的试验都以卡托普利为基准,卡托普利是一种标准的ACE抑制剂。结果表明,BMY 7378与ACE活性位点结合,但与Zn701的相互作用降低(与卡托普利相比为73.7 %),这可能是由于其氨基的pKa。bmy7378的抑制浓度50 (IC50)为136 μM,低于其他已报道的苯哌嗪衍生物。此外,BMY 7378显著增加SHR心脏中ACE的表达,与卡托普利相比增加了8.5倍。总之,BMY 7378具有α1D-AR拮抗剂和ACE抑制剂的双重活性,使其成为研究和潜在治疗高血压及其相关心血管并发症的药理工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biochimica et biophysica acta. General subjects
Biochimica et biophysica acta. General subjects 生物-生化与分子生物学
CiteScore
6.40
自引率
0.00%
发文量
139
审稿时长
30 days
期刊介绍: BBA General Subjects accepts for submission either original, hypothesis-driven studies or reviews covering subjects in biochemistry and biophysics that are considered to have general interest for a wide audience. Manuscripts with interdisciplinary approaches are especially encouraged.
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