Bioavailability studies and in vitro profiling of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-102)

Isabell Haym; T.H.V. Huyng; Stinne Wessel Hansen; M.H.F. Pedersen; J.A. Ruiz; Mette Norman Erichsen; M. Gynther; Walden Emil Bjørn-Yoshimoto; Bjarke Abrahamsen; Jesper F. Bastlund; Christoffer Bundgaard; A.L. Eriksen; Anders A. Jensen; Lennart Bunch

doi:10.1002/cmdc.201500527

Bioavailability studies and in vitro profiling of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-102)

Isabell Haym, T.H.V. Huyng, Stinne Wessel Hansen, M.H.F. Pedersen, J.A. Ruiz, Mette Norman Erichsen, M. Gynther, Walden Emil Bjørn-Yoshimoto, Bjarke Abrahamsen, Jesper F. Bastlund, Christoffer Bundgaard, A.L. Eriksen, Anders A. Jensen, Lennart Bunch

7 Citationer (Scopus)

Abstract

Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood–brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg−1) of the closely related analogue UCPH-102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH-102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH-102 (10 μm) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH-102 (20 mg kg−1) did not induce acute effects or any visible changes in behavior.

Originalsprog	Engelsk
Tidsskrift	ChemMedChem
Vol/bind	11
Udgave nummer	4
Sider (fra-til)	403-419
Antal sider	17
ISSN	1860-7179
DOI	https://doi.org/10.1002/cmdc.201500527
Status	Udgivet - 2016

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10.1002/cmdc.201500527

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Citationsformater

Haym, I., Huyng, T. H. V., Hansen, S. W., Pedersen, M. H. F., Ruiz, J. A., Erichsen, M. N., Gynther, M., Bjørn-Yoshimoto, W. E., Abrahamsen, B., Bastlund, J. F., Bundgaard, C., Eriksen, A. L., Jensen, A. A., & Bunch, L. (2016). Bioavailability studies and in vitro profiling of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-102). ChemMedChem, 11(4), 403-419. https://doi.org/10.1002/cmdc.201500527

Bioavailability studies and in vitro profiling of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-102). / Haym, Isabell; Huyng, T.H.V.; Hansen, Stinne Wessel et al.

I: ChemMedChem, Bind 11, Nr. 4, 2016, s. 403-419.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Haym, I, Huyng, THV, Hansen, SW, Pedersen, MHF, Ruiz, JA, Erichsen, MN, Gynther, M, Bjørn-Yoshimoto, WE, Abrahamsen, B, Bastlund, JF, Bundgaard, C, Eriksen, AL, Jensen, AA & Bunch, L 2016, 'Bioavailability studies and in vitro profiling of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-102)', ChemMedChem, bind 11, nr. 4, s. 403-419. https://doi.org/10.1002/cmdc.201500527

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title = "Bioavailability studies and in vitro profiling of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-102)",

abstract = "Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood–brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg−1) of the closely related analogue UCPH-102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH-102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH-102 (10 μm) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH-102 (20 mg kg−1) did not induce acute effects or any visible changes in behavior.",

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T1 - Bioavailability studies and in vitro profiling of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-102)

AU - Haym, Isabell

AU - Huyng, T.H.V.

AU - Hansen, Stinne Wessel

AU - Pedersen, M.H.F.

AU - Ruiz, J.A.

AU - Erichsen, Mette Norman

AU - Gynther, M.

AU - Bjørn-Yoshimoto, Walden Emil

AU - Abrahamsen, Bjarke

AU - Bastlund, Jesper F.

AU - Bundgaard, Christoffer

AU - Eriksen, A.L.

AU - Jensen, Anders A.

AU - Bunch, Lennart

PY - 2016

Y1 - 2016

N2 - Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood–brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg−1) of the closely related analogue UCPH-102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH-102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH-102 (10 μm) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH-102 (20 mg kg−1) did not induce acute effects or any visible changes in behavior.

AB - Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH-101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood–brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg−1) of the closely related analogue UCPH-102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH-102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH-102 (10 μm) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH-102 (20 mg kg−1) did not induce acute effects or any visible changes in behavior.

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DO - 10.1002/cmdc.201500527

M3 - Journal article

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SN - 1860-7179

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JO - Farmaco, Edizione Pratica

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