Partial agonist activity of α1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3.
Partial agonist activity of α1-adrenergic receptor antagonists for chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3.
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α1-肾上腺素能受体拮抗剂对趋化因子（C-X-C 矩阵）受体 4 和非典型趋化因子受体 3 的部分激动活性。
DOI：
10.1371/journal.pone.0204041
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Majetschak M
中科院分区：
文献类型：
--
作者：
Gao X;Abdelkarim H;Albee LJ;Volkman BF;Gaponenko V;Majetschak M
我们在PRESTO-Tango β-arrestin募集试验中观察到α1-肾上腺素能受体（AR）拮抗剂哌唑嗪激活趋化因子（C-X-C基序）受体（CXCR）4。这促使我们进一步研究这种意想不到的药理学行为。我们在PRESTO-Tango试验中针对同源激动剂CXCL 1/2筛选了一组14种α1/2-和β1/2/3-AR拮抗剂的CXCR 4和非典型趋化因子受体（ACKR）3激动剂活性。我们观察到多种α1-AR拮抗剂激活CXCR 4（CXCL 12 =哌唑嗪=环唑嗪>多沙唑嗪）和ACKR 3（CXCL 12 =哌唑嗪=环唑嗪>阿夫唑嗪=多沙唑嗪=酚妥拉明>特拉唑嗪=西洛多辛=坦索罗辛）。选择两种最强的CXCR 4/ACKR 3激活剂哌唑嗪和环唑嗪进行更详细的评价。我们发现，这些药物在β-arrestin募集试验中剂量依赖性地激活两种受体，刺激过表达每种受体的HEK 293细胞中的ERK 1/2磷酸化，并且它们对CXCR 4的作用可以被AMD 3100抑制。两种α1-AR拮抗剂均诱导膜中CXCR 4和ACKR 3的1H-13 C-杂环单量子相关光谱发生显著化学位移变化，表明受体结合。此外，哌唑嗪和环唑嗪诱导内源性CXCR 4/ACKR 3在人血管平滑肌细胞（hVSMC）的内化。虽然这些药物在hVSMC中不诱导趋化性，但它们以高功效和效力抑制CXCL 12诱导的趋化性（IC 50：哌唑嗪-4.5 nM，环唑嗪11.6 pM）。我们的研究结果揭示了哌唑嗪、环唑嗪和其他α1-AR拮抗剂的意料之外的药理学特性。本研究的结果表明，哌唑嗪和环唑嗪是偏向或部分CXCR 4/ACKR 3激动剂，其功能是有效的CXCL 12拮抗剂。我们的研究结果可以为先前观察到的α1-AR拮抗剂的抗癌特性提供机制基础，并支持哌唑嗪可以重新用于治疗CXCR 4和ACKR 3被认为发挥重要病理生理作用的疾病过程的概念，如癌症转移或各种自身免疫性病理。
We observed in PRESTO-Tango β-arrestin recruitment assays that the α1-adrenergic receptor (AR) antagonist prazosin activates chemokine (C-X-C motif) receptor (CXCR)4. This prompted us to further examine this unexpected pharmacological behavior. We screened a panel of 14 α1/2- and β1/2/3-AR antagonists for CXCR4 and atypical chemokine receptor (ACKR)3 agonist activity in PRESTO-Tango assays against the cognate agonist CXCL12. We observed that multiple α1-AR antagonists activate CXCR4 (CXCL12 = prazosin = cyclazosin > doxazosin) and ACKR3 (CXCL12 = prazosin = cyclazosin > alfuzosin = doxazosin = phentolamine > terazosin = silodosin = tamsulosin). The two strongest CXCR4/ACKR3 activators, prazosin and cyclazosin, were selected for a more detailed evaluation. We found that the drugs dose-dependently activate both receptors in β-arrestin recruitment assays, stimulate ERK1/2 phosphorylation in HEK293 cells overexpressing each receptor, and that their effects on CXCR4 could be inhibited with AMD3100. Both α1-AR antagonists induced significant chemical shift changes in the 1H-13C-heteronuclear single quantum correlation spectrum of CXCR4 and ACKR3 in membranes, suggesting receptor binding. Furthermore, prazosin and cyclazosin induced internalization of endogenous CXCR4/ACKR3 in human vascular smooth muscle cells (hVSMC). While these drugs did not in induce chemotaxis in hVSMC, they inhibited CXCL12-induced chemotaxis with high efficacy and potency (IC50: prazosin—4.5 nM, cyclazosin 11.6 pM). Our findings reveal unexpected pharmacological properties of prazosin, cyclazosin, and likely other α1-AR antagonists. The results of the present study imply that prazosin and cyclazosin are biased or partial CXCR4/ACKR3 agonists, which function as potent CXCL12 antagonists. Our findings could provide a mechanistic basis for previously observed anti-cancer properties of α1-AR antagonists and support the concept that prazosin could be re-purposed for the treatment of disease processes in which CXCR4 and ACKR3 are thought to play significant pathophysiological roles, such as cancer metastases or various autoimmune pathologies.
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