Structure-activity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations

Tri H. V. Huynh; Irene Shim; Henrik Bohr; Bjarke Abrahamsen; Birgitte Nielsen; Anders A. Jensen; Lennart Bunch

doi:10.1021/jm300345z

Structure-activity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations

Tri H. V. Huynh, Irene Shim, Henrik Bohr, Bjarke Abrahamsen, Birgitte Nielsen, Anders A. Jensen, Lennart Bunch

23 Citations (Scopus)

Abstract

The excitatory amino acid transporters (EAATs) play essential roles in regulating the synaptic concentration of the neurotransmitter glutamate in the mammalian central nervous system. To date, five subtypes have been identified, named EAAT1-5 in humans, and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5 in rodents, respectively. In this paper, we present the design, synthesis, and pharmacological evaluation of seven 7-N-substituted analogues of UCPH-101/102. Analogue 9 inhibited EAAT1 in the micromolar range (IC(50) value 20 µM), whereas analogues 8 and 10 were inactive (IC(50) values >100 µM). The diastereomeric pairs 11a/11b and 12a/12b were separated by HPLC and the absolute configuration assigned by VCD technique in combination with ab initio Hartree-Fock calculations. Analogues 11a (RS-isomer) and 12b (RR-isomer) inhibited EAAT1 (IC(50) values 5.5 and 3.8 µM, respectively), whereas analogues 11b (SS-isomer) and 12a (SR-isomer) failed to inhibit EAAT1 uptake (IC(50) values >300 µM).

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	55
Issue number	11
Pages (from-to)	5403-12
Number of pages	10
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm300345z
Publication status	Published - 14 Jun 2012

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Huynh, T. H. V., Shim, I., Bohr, H., Abrahamsen, B., Nielsen, B., Jensen, A. A., & Bunch, L. (2012). Structure-activity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations. Journal of Medicinal Chemistry, 55(11), 5403-12. https://doi.org/10.1021/jm300345z

Structure-activity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations. / Huynh, Tri H. V.; Shim, Irene; Bohr, Henrik et al.

In: Journal of Medicinal Chemistry, Vol. 55, No. 11, 14.06.2012, p. 5403-12.

Research output: Contribution to journal › Journal article › Research › peer-review

Huynh, THV, Shim, I, Bohr, H, Abrahamsen, B, Nielsen, B , Jensen, AA & Bunch, L 2012, 'Structure-activity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations', Journal of Medicinal Chemistry, vol. 55, no. 11, pp. 5403-12. https://doi.org/10.1021/jm300345z

Huynh THV, Shim I, Bohr H, Abrahamsen B, Nielsen B , Jensen AA et al. Structure-activity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations. Journal of Medicinal Chemistry. 2012 Jun 14;55(11):5403-12. doi: 10.1021/jm300345z

Huynh, Tri H. V. ; Shim, Irene ; Bohr, Henrik et al. / Structure-activity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 11. pp. 5403-12.

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title = "Structure-activity relationship study of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and absolute configurational assignment using infrared and vibrational circular dichroism spectroscopy in combination with ab initio hartree-fock calculations",

abstract = "The excitatory amino acid transporters (EAATs) play essential roles in regulating the synaptic concentration of the neurotransmitter glutamate in the mammalian central nervous system. To date, five subtypes have been identified, named EAAT1-5 in humans, and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5 in rodents, respectively. In this paper, we present the design, synthesis, and pharmacological evaluation of seven 7-N-substituted analogues of UCPH-101/102. Analogue 9 inhibited EAAT1 in the micromolar range (IC(50) value 20 µM), whereas analogues 8 and 10 were inactive (IC(50) values >100 µM). The diastereomeric pairs 11a/11b and 12a/12b were separated by HPLC and the absolute configuration assigned by VCD technique in combination with ab initio Hartree-Fock calculations. Analogues 11a (RS-isomer) and 12b (RR-isomer) inhibited EAAT1 (IC(50) values 5.5 and 3.8 µM, respectively), whereas analogues 11b (SS-isomer) and 12a (SR-isomer) failed to inhibit EAAT1 uptake (IC(50) values >300 µM).",

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AU - Huynh, Tri H. V.

AU - Shim, Irene

AU - Bohr, Henrik

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AU - Nielsen, Birgitte

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AB - The excitatory amino acid transporters (EAATs) play essential roles in regulating the synaptic concentration of the neurotransmitter glutamate in the mammalian central nervous system. To date, five subtypes have been identified, named EAAT1-5 in humans, and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5 in rodents, respectively. In this paper, we present the design, synthesis, and pharmacological evaluation of seven 7-N-substituted analogues of UCPH-101/102. Analogue 9 inhibited EAAT1 in the micromolar range (IC(50) value 20 µM), whereas analogues 8 and 10 were inactive (IC(50) values >100 µM). The diastereomeric pairs 11a/11b and 12a/12b were separated by HPLC and the absolute configuration assigned by VCD technique in combination with ab initio Hartree-Fock calculations. Analogues 11a (RS-isomer) and 12b (RR-isomer) inhibited EAAT1 (IC(50) values 5.5 and 3.8 µM, respectively), whereas analogues 11b (SS-isomer) and 12a (SR-isomer) failed to inhibit EAAT1 uptake (IC(50) values >300 µM).

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