4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues

Marco L Lolli; Cecilia Giordano; Darryl S Pickering; Barbara Rolando; Kasper B Hansen; Antonio Foti; Alberto Contreras-Sanz; Ahmad Amir; Roberta Fruttero; Alberto Gasco; Birgitte Nielsen; Tommy N Johansen

doi:10.1021/jm1001452

4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues

Marco L Lolli, Cecilia Giordano, Darryl S Pickering, Barbara Rolando, Kasper B Hansen, Antonio Foti, Alberto Contreras-Sanz, Ahmad Amir, Roberta Fruttero, Alberto Gasco, Birgitte Nielsen, Tommy N Johansen

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

28 Citationer (Scopus)

Abstract

Udgivelsesdato: 2010-May-27

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	53
Udgave nummer	10
Sider (fra-til)	4110-8
Antal sider	8
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm1001452
Status	Udgivet - 2010

Adgang til dokumentet

10.1021/jm1001452

Citationsformater

Lolli, M. L., Giordano, C., Pickering, D. S., Rolando, B., Hansen, K. B., Foti, A., Contreras-Sanz, A., Amir, A., Fruttero, R., Gasco, A., Nielsen, B., & Johansen, T. N. (2010). 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues. Journal of Medicinal Chemistry, 53(10), 4110-8. https://doi.org/10.1021/jm1001452

4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues. / Lolli, Marco L; Giordano, Cecilia; Pickering, Darryl S et al.
I: Journal of Medicinal Chemistry, Bind 53, Nr. 10, 2010, s. 4110-8.

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

Lolli, ML, Giordano, C, Pickering, DS, Rolando, B, Hansen, KB, Foti, A, Contreras-Sanz, A, Amir, A, Fruttero, R, Gasco, A, Nielsen, B & Johansen, TN 2010, '4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues', Journal of Medicinal Chemistry, bind 53, nr. 10, s. 4110-8. https://doi.org/10.1021/jm1001452

Lolli ML, Giordano C, Pickering DS, Rolando B, Hansen KB, Foti A et al. 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues. Journal of Medicinal Chemistry. 2010;53(10):4110-8. doi: 10.1021/jm1001452

Lolli, Marco L ; Giordano, Cecilia ; Pickering, Darryl S et al. / 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues. I: Journal of Medicinal Chemistry. 2010 ; Bind 53, Nr. 10. s. 4110-8.

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title = "4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues",

abstract = "In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.",

author = "Lolli, {Marco L} and Cecilia Giordano and Pickering, {Darryl S} and Barbara Rolando and Hansen, {Kasper B} and Antonio Foti and Alberto Contreras-Sanz and Ahmad Amir and Roberta Fruttero and Alberto Gasco and Birgitte Nielsen and Johansen, {Tommy N}",

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doi = "10.1021/jm1001452",

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T1 - 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological characterization at ionotropic glutamate receptors of compounds related to glutamate and its homologues

AU - Lolli, Marco L

AU - Giordano, Cecilia

AU - Pickering, Darryl S

AU - Rolando, Barbara

AU - Hansen, Kasper B

AU - Foti, Antonio

AU - Contreras-Sanz, Alberto

AU - Amir, Ahmad

AU - Fruttero, Roberta

AU - Gasco, Alberto

AU - Nielsen, Birgitte

AU - Johansen, Tommy N

PY - 2010

Y1 - 2010

N2 - In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.

AB - In order to investigate the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as a carboxylic acid bioisoster at ionotropic glutamate receptors (iGluRs), a series of acidic alpha-aminocarboxylic acids in which the distal carboxy group was replaced by the 4-hydroxy-1,2,5-oxadiazol-3-yl group was synthesized. Ionization constants were determined. All target compounds, except the Asp analogue 12, were resolved using chiral HPLC. Whereas 12 showed good affinity exclusively at NMDA receptors, the Glu analogue, (+)-10, was an unselective, though potent AMPA receptor preferring agonist (EC(50) = 10 microM at iGluR2) showing only low stereoselectivity. The two higher Glu homologues, (+)-15 and (+)-18, turned out to be weak agonists at iGluR2 as well as weak antagonists at NR1/NR2A, whereas the corresponding (-)-isomers were selective NR1/NR2A antagonists with somewhat higher potency. The results proved the 4-hydroxy-1,2,5-oxadiazol-3-yl moiety to be a useful bioisoster at all three classes of iGluRs, capable of being integrated into agonists as well as antagonists.

U2 - 10.1021/jm1001452

DO - 10.1021/jm1001452

M3 - Journal article

C2 - 20408529

SN - 0022-2623

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

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