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Effects of SRI-32743, a Novel Quinazoline Structure-Based Compound, on HIV-1 Tat and Cocaine Interaction with Norepinephrine Transporter
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Effects of SRI-32743, a Novel Quinazoline Structure-Based Compound, on HIV-1 Tat and Cocaine Interaction with Norepinephrine Transporter
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Effects of SRI-32743, a Novel Quinazoline Structure-Based Compound, on HIV-1 Tat and Cocaine Interaction with Norepinephrine Transporter
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Journal Article
Effects of SRI-32743, a Novel Quinazoline Structure-Based Compound, on HIV-1 Tat and Cocaine Interaction with Norepinephrine Transporter
2024
Overview
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 [3H]DA uptake but preserved the Vmax of dopamine transport. SRI-32743 slowed the cocaine-mediated dissociation of [3H]Nisoxetine binding and reduced both [3H]DA and [3H]MPP+ efflux but did not affect d-amphetamine-mediated [3H]DA release through hNET. Finally, we determined that SRI-32743 attenuated a recombinant Tat1–86-induced decrease in [3H]DA uptake via hNET. Our findings demonstrated that SRI-32743 allosterically disrupts the recombinant Tat1–86–hNET interaction, suggesting a potential treatment for HIV-infected individuals with concurrent cocaine abuse.
Publisher
MDPI AG
Subject
/ Animals
/ Cocaine
/ Dopamine
/ Dopamine Plasma Membrane Transport Proteins - metabolism
/ Highly active antiretroviral therapy
/ HIV
/ Human immunodeficiency virus
/ Humans
/ Mice
/ Norepinephrine Plasma Membrane Transport Proteins - metabolism
/ tat Gene Products, Human Immunodeficiency Virus - chemistry
/ tat Gene Products, Human Immunodeficiency Virus - metabolism
