Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, 715 Sumter Street, Columbia, SC 29208, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Int J Mol Sci. 2024 Jul 18;25(14):7881. doi: 10.3390/ijms25147881.
Prolonged exposure to HIV-1 transactivator of transcription (Tat) protein dysregulates monoamine transmission, a physiological change implicated as a key factor in promoting neurocognitive disorders among people living with HIV. We have demonstrated that in vivo expression of Tat in Tat transgenic mice decreases dopamine uptake through both dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex. Further, our novel allosteric inhibitor of monoamine transporters, SRI-32743, has been shown to attenuate Tat-inhibited dopamine transport through DAT and alleviates Tat-potentiated cognitive impairments. The current study reports the pharmacological profiles of SRI-32743 in basal and Tat-induced inhibition of human NET (hNET) function. SRI-32743 exhibited less affinity for hNET binding than desipramine, a classical NET inhibitor, but displayed similar potency for inhibiting hDAT and hNET activity. SRI-32743 concentration-dependently increased hNET affinity for [H]DA uptake but preserved the V of dopamine transport. SRI-32743 slowed the cocaine-mediated dissociation of [H]Nisoxetine binding and reduced both [H]DA and [H]MPP+ efflux but did not affect d-amphetamine-mediated [H]DA release through hNET. Finally, we determined that SRI-32743 attenuated a recombinant Tat-induced decrease in [H]DA uptake via hNET. Our findings demonstrated that SRI-32743 allosterically disrupts the recombinant Tat-hNET interaction, suggesting a potential treatment for HIV-infected individuals with concurrent cocaine abuse.
长期暴露于 HIV-1 转录激活物（Tat）蛋白会导致单胺递质传递失调，这种生理变化被认为是促进 HIV 感染者发生神经认知障碍的关键因素。我们已经证明，在 Tat 转基因小鼠中体内表达 Tat 通过前额叶皮层中的多巴胺转运体（DAT）和去甲肾上腺素转运体（NET）降低多巴胺摄取。此外，我们新型的单胺转运体别构抑制剂 SRI-32743 已被证明可减轻 Tat 抑制的多巴胺转运通过 DAT，并缓解 Tat 增强的认知障碍。本研究报告了 SRI-32743 在基础状态和 Tat 诱导的人 NET（hNET）功能抑制中的药理学特征。SRI-32743 对 hNET 结合的亲和力低于经典 NET 抑制剂去甲丙咪嗪，但对抑制 hDAT 和 hNET 活性的效力相似。SRI-32743 浓度依赖性地增加 hNET 对 [H]DA 摄取的亲和力，但保留多巴胺转运的 V。SRI-32743 减缓可卡因介导的 [H]Nisoxetine 结合解离，并减少 [H]DA 和 [H]MPP+外排，但不影响通过 hNET 的 d-苯丙胺介导的 [H]DA 释放。最后，我们确定 SRI-32743 减轻了重组 Tat 诱导的 hNET 介导的 [H]DA 摄取减少。我们的研究结果表明，SRI-32743 别构破坏了重组 Tat-hNET 相互作用，提示对合并可卡因滥用的 HIV 感染者具有潜在的治疗作用。
