Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram

Gisela Andrea Camacho-Hernandez; Andrea Casiraghi; Deborah Rudin; Dino Luethi; Therese C. Ku; Daryl A. Guthrie; Valentina Straniero; Ermanno Valoti; Gerhard J. Schütz; Harald H. Sitte; Amy Hauck Newman

doi:10.1039/d1md00072a

Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram

Gisela Andrea Camacho-Hernandez, Andrea Casiraghi, Deborah Rudin, Dino Luethi, Therese C. Ku, Daryl A. Guthrie, Valentina Straniero, Ermanno Valoti, Gerhard J. Schütz, Harald H. Sitte, Amy Hauck Newman

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

The utilization of fluorescent ligands to study the monoamine transporters (MATs) has increased our knowledge of their function and distribution in live cell systems. In this study, we extend SAR for nisoxetine and talopram as parent compounds, to identify high affinity rhodamine-labeled fluorescent probes for the norepinephrine transporter (NET). Nisoxetine-based fluorescent probe6demonstrated high binding affinity (K_i= 43 nM) for NET and an overall selectivity compared to the other transporters for dopamine (DAT;K_i= 1540 nM) and serotonin (SERT;K_i= 785 nM) in competitive radioligand binding assays. Using confocal microscopy, compound6was shown to stain both NET and SERT, but not DAT, at low nanomolar concentrations, in transporter-expressing cells.

Original language	English (US)
Pages (from-to)	1174-1186
Number of pages	13
Journal	RSC Medicinal Chemistry
Volume	12
Issue number	7
DOIs	https://doi.org/10.1039/d1md00072a
State	Published - Jul 2021
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

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10.1039/d1md00072a

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title = "Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram",

abstract = "The utilization of fluorescent ligands to study the monoamine transporters (MATs) has increased our knowledge of their function and distribution in live cell systems. In this study, we extend SAR for nisoxetine and talopram as parent compounds, to identify high affinity rhodamine-labeled fluorescent probes for the norepinephrine transporter (NET). Nisoxetine-based fluorescent probe6demonstrated high binding affinity (Ki= 43 nM) for NET and an overall selectivity compared to the other transporters for dopamine (DAT;Ki= 1540 nM) and serotonin (SERT;Ki= 785 nM) in competitive radioligand binding assays. Using confocal microscopy, compound6was shown to stain both NET and SERT, but not DAT, at low nanomolar concentrations, in transporter-expressing cells.",

author = "Camacho-Hernandez, {Gisela Andrea} and Andrea Casiraghi and Deborah Rudin and Dino Luethi and Ku, {Therese C.} and Guthrie, {Daryl A.} and Valentina Straniero and Ermanno Valoti and Sch{\"u}tz, {Gerhard J.} and Sitte, {Harald H.} and Newman, {Amy Hauck}",

note = "Publisher Copyright: {\textcopyright} The Royal Society of Chemistry 2021.",

year = "2021",

month = jul,

doi = "10.1039/d1md00072a",

language = "English (US)",

volume = "12",

pages = "1174--1186",

journal = "RSC Medicinal Chemistry",

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publisher = "Royal Society of Chemistry",

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T1 - Illuminating the norepinephrine transporter

T2 - fluorescent probes based on nisoxetine and talopram

AU - Camacho-Hernandez, Gisela Andrea

AU - Casiraghi, Andrea

AU - Rudin, Deborah

AU - Luethi, Dino

AU - Ku, Therese C.

AU - Guthrie, Daryl A.

AU - Straniero, Valentina

AU - Valoti, Ermanno

AU - Schütz, Gerhard J.

AU - Sitte, Harald H.

AU - Newman, Amy Hauck

PY - 2021/7

Y1 - 2021/7

N2 - The utilization of fluorescent ligands to study the monoamine transporters (MATs) has increased our knowledge of their function and distribution in live cell systems. In this study, we extend SAR for nisoxetine and talopram as parent compounds, to identify high affinity rhodamine-labeled fluorescent probes for the norepinephrine transporter (NET). Nisoxetine-based fluorescent probe6demonstrated high binding affinity (Ki= 43 nM) for NET and an overall selectivity compared to the other transporters for dopamine (DAT;Ki= 1540 nM) and serotonin (SERT;Ki= 785 nM) in competitive radioligand binding assays. Using confocal microscopy, compound6was shown to stain both NET and SERT, but not DAT, at low nanomolar concentrations, in transporter-expressing cells.

AB - The utilization of fluorescent ligands to study the monoamine transporters (MATs) has increased our knowledge of their function and distribution in live cell systems. In this study, we extend SAR for nisoxetine and talopram as parent compounds, to identify high affinity rhodamine-labeled fluorescent probes for the norepinephrine transporter (NET). Nisoxetine-based fluorescent probe6demonstrated high binding affinity (Ki= 43 nM) for NET and an overall selectivity compared to the other transporters for dopamine (DAT;Ki= 1540 nM) and serotonin (SERT;Ki= 785 nM) in competitive radioligand binding assays. Using confocal microscopy, compound6was shown to stain both NET and SERT, but not DAT, at low nanomolar concentrations, in transporter-expressing cells.

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Illuminating the norepinephrine transporter: fluorescent probes based on nisoxetine and talopram

Abstract

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