The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue: synthesis, molecular pharmacology, and biostructural characterization

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

Standard

The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue : synthesis, molecular pharmacology, and biostructural characterization. / Clausen, Rasmus Prætorius; Naur, Peter; Kristensen, Anders Skov; Greenwood, Jeremy R; Strange, Mette; Bräuner-Osborne, Hans; Jensen, Anders Asbjørn; Nielsen, Anne Sophie T; Geneser, Ulla; Ringgaard, Lone M; Nielsen, Birgitte; Pickering, Darryl S; Brehm, Lotte; Gajhede, Michael; Krogsgaard-Larsen, Povl; Kastrup, Jette Sandholm.

In: Journal of Medicinal Chemistry, Vol. 52, No. 15, 2009, p. 4911-4922.

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

Harvard

Clausen, RP, Naur, P, Kristensen, AS, Greenwood, JR, Strange, M, Bräuner-Osborne, H, Jensen, AA, Nielsen, AST, Geneser, U, Ringgaard, LM, Nielsen, B, Pickering, DS, Brehm, L, Gajhede, M, Krogsgaard-Larsen, P & Kastrup, JS 2009, 'The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue: synthesis, molecular pharmacology, and biostructural characterization', Journal of Medicinal Chemistry, vol. 52, no. 15, pp. 4911-4922. https://doi.org/10.1021/jm900565c

APA

Clausen, R. P., Naur, P., Kristensen, A. S., Greenwood, J. R., Strange, M., Bräuner-Osborne, H., Jensen, A. A., Nielsen, A. S. T., Geneser, U., Ringgaard, L. M., Nielsen, B., Pickering, D. S., Brehm, L., Gajhede, M., Krogsgaard-Larsen, P., & Kastrup, J. S. (2009). The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue: synthesis, molecular pharmacology, and biostructural characterization. Journal of Medicinal Chemistry, 52(15), 4911-4922. https://doi.org/10.1021/jm900565c

Vancouver

Clausen RP, Naur P, Kristensen AS, Greenwood JR, Strange M, Bräuner-Osborne H et al. The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue: synthesis, molecular pharmacology, and biostructural characterization. Journal of Medicinal Chemistry. 2009;52(15):4911-4922. https://doi.org/10.1021/jm900565c

Author

Clausen, Rasmus Prætorius ; Naur, Peter ; Kristensen, Anders Skov ; Greenwood, Jeremy R ; Strange, Mette ; Bräuner-Osborne, Hans ; Jensen, Anders Asbjørn ; Nielsen, Anne Sophie T ; Geneser, Ulla ; Ringgaard, Lone M ; Nielsen, Birgitte ; Pickering, Darryl S ; Brehm, Lotte ; Gajhede, Michael ; Krogsgaard-Larsen, Povl ; Kastrup, Jette Sandholm. / The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue : synthesis, molecular pharmacology, and biostructural characterization. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 15. pp. 4911-4922.

Bibtex

@article{f84fc4e0af2d11debc73000ea68e967b,
title = "The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue: synthesis, molecular pharmacology, and biostructural characterization",
abstract = "The design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (iGluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously demonstrated for 4. An X-ray crystallographic analysis of 4 and computational analyses of 4 and 5 bound to the GluR5 agonist binding domain (ABD) are presented, including a watermap analysis, which suggests that water molecules in the agonist binding site are important selectivity determinants.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Clausen, {Rasmus Pr{\ae}torius} and Peter Naur and Kristensen, {Anders Skov} and Greenwood, {Jeremy R} and Mette Strange and Hans Br{\"a}uner-Osborne and Jensen, {Anders Asbj{\o}rn} and Nielsen, {Anne Sophie T} and Ulla Geneser and Ringgaard, {Lone M} and Birgitte Nielsen and Pickering, {Darryl S} and Lotte Brehm and Michael Gajhede and Povl Krogsgaard-Larsen and Kastrup, {Jette Sandholm}",
note = "Keywords: Animals; Cell Line; Crystallography, X-Ray; Drug Design; Excitatory Amino Acid Agonists; Humans; Models, Molecular; Propionic Acids; Receptors, Kainic Acid; Stereoisomerism; Structure-Activity Relationship; Xenopus laevis",
year = "2009",
doi = "10.1021/jm900565c",
language = "English",
volume = "52",
pages = "4911--4922",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "15",

}

RIS

TY - JOUR

T1 - The glutamate receptor GluR5 agonist (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid and the 8-methyl analogue

T2 - synthesis, molecular pharmacology, and biostructural characterization

AU - Clausen, Rasmus Prætorius

AU - Naur, Peter

AU - Kristensen, Anders Skov

AU - Greenwood, Jeremy R

AU - Strange, Mette

AU - Bräuner-Osborne, Hans

AU - Jensen, Anders Asbjørn

AU - Nielsen, Anne Sophie T

AU - Geneser, Ulla

AU - Ringgaard, Lone M

AU - Nielsen, Birgitte

AU - Pickering, Darryl S

AU - Brehm, Lotte

AU - Gajhede, Michael

AU - Krogsgaard-Larsen, Povl

AU - Kastrup, Jette Sandholm

N1 - Keywords: Animals; Cell Line; Crystallography, X-Ray; Drug Design; Excitatory Amino Acid Agonists; Humans; Models, Molecular; Propionic Acids; Receptors, Kainic Acid; Stereoisomerism; Structure-Activity Relationship; Xenopus laevis

PY - 2009

Y1 - 2009

N2 - The design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (iGluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously demonstrated for 4. An X-ray crystallographic analysis of 4 and computational analyses of 4 and 5 bound to the GluR5 agonist binding domain (ABD) are presented, including a watermap analysis, which suggests that water molecules in the agonist binding site are important selectivity determinants.

AB - The design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (iGluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously demonstrated for 4. An X-ray crystallographic analysis of 4 and computational analyses of 4 and 5 bound to the GluR5 agonist binding domain (ABD) are presented, including a watermap analysis, which suggests that water molecules in the agonist binding site are important selectivity determinants.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1021/jm900565c

DO - 10.1021/jm900565c

M3 - Journal article

C2 - 19588945

VL - 52

SP - 4911

EP - 4922

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 15

ER -

ID: 14879907