Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues

Shuang-Yan Wang; Younes Larsen; Cristina V. Navarrete; Anders A. Jensen; Birgitte Nielsen; Ali Al-Musaed; Karla Frydenvang; Jette Sandholm Kastrup; Darryl S Pickering; Rasmus Prætorius Clausen

doi:10.1021/acs.jmedchem.5b01982

Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues

Shuang-Yan Wang, Younes Larsen, Cristina V. Navarrete, Anders A. Jensen, Birgitte Nielsen, Ali Al-Musaed, Karla Frydenvang, Jette Sandholm Kastrup, Darryl S Pickering, Rasmus Prætorius Clausen

3 Citations (Scopus)

Abstract

A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	5
Pages (from-to)	2244-2254
Number of pages	11
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.5b01982
Publication status	Published - 10 Mar 2016

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Wang, S.-Y., Larsen, Y., Navarrete, C. V., Jensen, A. A., Nielsen, B., Al-Musaed, A., Frydenvang, K., Kastrup, J. S., Pickering, D. S., & Clausen, R. P. (2016). Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues. Journal of Medicinal Chemistry, 59(5), 2244-2254. https://doi.org/10.1021/acs.jmedchem.5b01982

Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues. / Wang, Shuang-Yan; Larsen, Younes; Navarrete, Cristina V. et al.
In: Journal of Medicinal Chemistry, Vol. 59, No. 5, 10.03.2016, p. 2244-2254.

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

Wang, S-Y, Larsen, Y, Navarrete, CV, Jensen, AA , Nielsen, B, Al-Musaed, A, Frydenvang, K , Kastrup, JS , Pickering, DS & Clausen, RP 2016, 'Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues', Journal of Medicinal Chemistry, vol. 59, no. 5, pp. 2244-2254. https://doi.org/10.1021/acs.jmedchem.5b01982

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title = "Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues",

abstract = "A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain.",

author = "Shuang-Yan Wang and Younes Larsen and Navarrete, {Cristina V.} and Jensen, {Anders A.} and Birgitte Nielsen and Ali Al-Musaed and Karla Frydenvang and Kastrup, {Jette Sandholm} and Pickering, {Darryl S} and Clausen, {Rasmus Pr{\ae}torius}",

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doi = "10.1021/acs.jmedchem.5b01982",

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T1 - Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues

AU - Wang, Shuang-Yan

AU - Larsen, Younes

AU - Navarrete, Cristina V.

AU - Jensen, Anders A.

AU - Nielsen, Birgitte

AU - Al-Musaed, Ali

AU - Frydenvang, Karla

AU - Kastrup, Jette Sandholm

AU - Pickering, Darryl S

AU - Clausen, Rasmus Prætorius

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N2 - A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain.

AB - A series of analogues of the (S)-2-Amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptor agonist BnTetAMPA (5b) were synthesized and characterized pharmacologically in radioligand binding assays at native and cloned AMPA receptors and functionally by two-electrode voltage clamp electrophysiology at the four homomeric AMPA receptors expressed in Xenopus laevis oocytes. The analogues 6 and 7 exhibit very different pharmacological profiles with binding affinity preference for the subtypes GluA1 and GluA3, respectively. X-ray crystal structures of three ligands (6, 7, and 8) in complex with the agonist binding domain (ABD) of GluA2 show that they induce full domain closure despite their low agonist efficacies. Trp767 in GluA2 ABD could be an important determinant for partial agonism of this compound series at AMPA receptors, since agonist efficacy also correlated with the location of the Trp767 side chain.

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DO - 10.1021/acs.jmedchem.5b01982

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C2 - 26862980

SN - 0022-2623

VL - 59

SP - 2244

EP - 2254

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 5

ER -

Tweaking subtype-selectivity and agonist efficacy at (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) receptors in a small series of BnTetAMPA analogues

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