Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid

Karla Andrea Frydenvang; Darryl S Pickering; Jeremy R Greenwood; Niels Krogsgaard-Larsen; Lotte Brehm; Birgitte Nielsen; Stine Byskov Vogensen; Helle Hald; Jette Sandholm Kastrup; Povl Krogsgaard-Larsen; Rasmus Prætorius Clausen

doi:10.1021/jm101218a

Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid

Karla Andrea Frydenvang, Darryl S Pickering, Jeremy R Greenwood, Niels Krogsgaard-Larsen, Lotte Brehm, Birgitte Nielsen, Stine Byskov Vogensen, Helle Hald, Jette Sandholm Kastrup, Povl Krogsgaard-Larsen, Rasmus Prætorius Clausen

16 Citations (Scopus)

Abstract

We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at AMPA receptor subtypes. Compound 5 was shown to be a subtype-discriminating agonist at AMPA receptors with higher binding affinity and functional potency at GluA1/2 compared to GluA3/4, unlike the isomeric analogue (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA, 4) that binds to all AMPA receptor subtypes with comparable potency. Biostructural X-ray crystallographic studies of 4 and 5 reveal different binding modes of (R)-4 and (S)-5 in the GluA2 agonist binding domain. WaterMap analysis of the GluA2 and GluA4 binding pockets with (R)-4 and (S)-5 suggests that the energy of hydration sites is ligand dependent, which may explain the observed selectivity.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	23
Pages (from-to)	8354-8361
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm101218a
Publication status	Published - 9 Dec 2010

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Frydenvang, K. A., Pickering, D. S., Greenwood, J. R., Krogsgaard-Larsen, N., Brehm, L., Nielsen, B., Vogensen, S. B., Hald, H., Kastrup, J. S., Krogsgaard-Larsen, P., & Clausen, R. P. (2010). Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid. Journal of Medicinal Chemistry, 53(23), 8354-8361. https://doi.org/10.1021/jm101218a

Frydenvang, KA , Pickering, DS, Greenwood, JR, Krogsgaard-Larsen, N, Brehm, L, Nielsen, B, Vogensen, SB, Hald, H, Kastrup, JS , Krogsgaard-Larsen, P & Clausen, RP 2010, 'Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid', Journal of Medicinal Chemistry, vol. 53, no. 23, pp. 8354-8361. https://doi.org/10.1021/jm101218a

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title = "Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid",

abstract = "We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at AMPA receptor subtypes. Compound 5 was shown to be a subtype-discriminating agonist at AMPA receptors with higher binding affinity and functional potency at GluA1/2 compared to GluA3/4, unlike the isomeric analogue (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA, 4) that binds to all AMPA receptor subtypes with comparable potency. Biostructural X-ray crystallographic studies of 4 and 5 reveal different binding modes of (R)-4 and (S)-5 in the GluA2 agonist binding domain. WaterMap analysis of the GluA2 and GluA4 binding pockets with (R)-4 and (S)-5 suggests that the energy of hydration sites is ligand dependent, which may explain the observed selectivity.",

author = "Frydenvang, {Karla Andrea} and Pickering, {Darryl S} and Greenwood, {Jeremy R} and Niels Krogsgaard-Larsen and Lotte Brehm and Birgitte Nielsen and Vogensen, {Stine Byskov} and Helle Hald and Kastrup, {Jette Sandholm} and Povl Krogsgaard-Larsen and Clausen, {Rasmus Pr{\ae}torius}",

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AU - Frydenvang, Karla Andrea

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AU - Greenwood, Jeremy R

AU - Krogsgaard-Larsen, Niels

AU - Brehm, Lotte

AU - Nielsen, Birgitte

AU - Vogensen, Stine Byskov

AU - Hald, Helle

AU - Kastrup, Jette Sandholm

AU - Krogsgaard-Larsen, Povl

AU - Clausen, Rasmus Prætorius

PY - 2010/12/9

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N2 - We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at AMPA receptor subtypes. Compound 5 was shown to be a subtype-discriminating agonist at AMPA receptors with higher binding affinity and functional potency at GluA1/2 compared to GluA3/4, unlike the isomeric analogue (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA, 4) that binds to all AMPA receptor subtypes with comparable potency. Biostructural X-ray crystallographic studies of 4 and 5 reveal different binding modes of (R)-4 and (S)-5 in the GluA2 agonist binding domain. WaterMap analysis of the GluA2 and GluA4 binding pockets with (R)-4 and (S)-5 suggests that the energy of hydration sites is ligand dependent, which may explain the observed selectivity.

AB - We describe an improved synthesis and detailed pharmacological characterization of the conformationally restricted analogue of the naturally occurring nonselective glutamate receptor agonist ibotenic acid (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA, 5) at AMPA receptor subtypes. Compound 5 was shown to be a subtype-discriminating agonist at AMPA receptors with higher binding affinity and functional potency at GluA1/2 compared to GluA3/4, unlike the isomeric analogue (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA, 4) that binds to all AMPA receptor subtypes with comparable potency. Biostructural X-ray crystallographic studies of 4 and 5 reveal different binding modes of (R)-4 and (S)-5 in the GluA2 agonist binding domain. WaterMap analysis of the GluA2 and GluA4 binding pockets with (R)-4 and (S)-5 suggests that the energy of hydration sites is ligand dependent, which may explain the observed selectivity.

U2 - 10.1021/jm101218a

DO - 10.1021/jm101218a

M3 - Journal article

C2 - 21067182

SN - 0022-2623

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SP - 8354

EP - 8361

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -

Biostructural and pharmacological studies of bicyclic analogues of the 3-isoxazolol glutamate receptor agonist ibotenic acid

Abstract

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