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 Citations (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.

Original language	English
Journal	ChemMedChem
Volume	11
Issue number	4
Pages (from-to)	403-419
Number of pages	17
ISSN	1860-7179
DOIs	https://doi.org/10.1002/cmdc.201500527
Publication status	Published - 2016

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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.

In: ChemMedChem, Vol. 11, No. 4, 2016, p. 403-419.

Research output: Contribution to journal › Journal article › Research › 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, vol. 11, no. 4, pp. 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.",

author = "Isabell Haym and T.H.V. Huyng and Hansen, {Stinne Wessel} and M.H.F. Pedersen and J.A. Ruiz and Erichsen, {Mette Norman} and M. Gynther and Bj{\o}rn-Yoshimoto, {Walden Emil} and Bjarke Abrahamsen and Bastlund, {Jesper F.} and Christoffer Bundgaard and A.L. Eriksen and Jensen, {Anders A.} and Lennart Bunch",

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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

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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

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JO - Farmaco, Edizione Pratica

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