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

Rasmus Prætorius Clausen; Peter Naur; Anders Skov Kristensen; Jeremy R Greenwood; Mette Strange; Hans Bräuner-Osborne; Anders Asbjørn Jensen; Anne Sophie T Nielsen; Ulla Geneser; Lone M Ringgaard; Birgitte Nielsen; Darryl S Pickering; Lotte Brehm; Michael Gajhede; Povl Krogsgaard-Larsen; Jette Sandholm Kastrup

doi:10.1021/jm900565c

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

Rasmus Prætorius Clausen, Peter Naur, Anders Skov Kristensen, Jeremy R Greenwood, Mette Strange, Hans Bräuner-Osborne, Anders Asbjørn Jensen, Anne Sophie T Nielsen, Ulla Geneser, Lone M Ringgaard, Birgitte Nielsen, Darryl S Pickering, Lotte Brehm, Michael Gajhede, Povl Krogsgaard-Larsen, Jette Sandholm Kastrup

20 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	52
Udgave nummer	15
Sider (fra-til)	4911-4922
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm900565c
Status	Udgivet - 2009

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Citationsformater

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

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 et al.
I: Journal of Medicinal Chemistry, Bind 52, Nr. 15, 2009, s. 4911-4922.

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

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, bind 52, nr. 15, s. 4911-4922. https://doi.org/10.1021/jm900565c

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. doi: 10.1021/jm900565c

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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.",

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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",

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doi = "10.1021/jm900565c",

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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

SN - 0022-2623

VL - 52

SP - 4911

EP - 4922

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -