(S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors

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Standard

(S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors. / Ahmadian, H; Nielsen, B; Bräuner-Osborne, Hans; Johansen, T N; Stensbøl, T B; Sløk, F A; Sekiyama, N; Nakanishi, S; Krogsgaard-Larsen, P; Madsen, U.

In: Journal of Medicinal Chemistry, Vol. 40, No. 22, 24.10.1997, p. 3700-5.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Ahmadian, H, Nielsen, B, Bräuner-Osborne, H, Johansen, TN, Stensbøl, TB, Sløk, FA, Sekiyama, N, Nakanishi, S, Krogsgaard-Larsen, P & Madsen, U 1997, '(S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors', Journal of Medicinal Chemistry, vol. 40, no. 22, pp. 3700-5. https://doi.org/10.1021/jm9703597

APA

Ahmadian, H., Nielsen, B., Bräuner-Osborne, H., Johansen, T. N., Stensbøl, T. B., Sløk, F. A., ... Madsen, U. (1997). (S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors. Journal of Medicinal Chemistry, 40(22), 3700-5. https://doi.org/10.1021/jm9703597

Vancouver

Ahmadian H, Nielsen B, Bräuner-Osborne H, Johansen TN, Stensbøl TB, Sløk FA et al. (S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors. Journal of Medicinal Chemistry. 1997 Oct 24;40(22):3700-5. https://doi.org/10.1021/jm9703597

Author

Ahmadian, H ; Nielsen, B ; Bräuner-Osborne, Hans ; Johansen, T N ; Stensbøl, T B ; Sløk, F A ; Sekiyama, N ; Nakanishi, S ; Krogsgaard-Larsen, P ; Madsen, U. / (S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 22. pp. 3700-5.

Bibtex

@article{affeba233f0d466fb0338c96cb0dd955,
title = "(S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors",
abstract = "Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu6 subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist for the pharmacological characterization of mGlu6 (Trends Pharmacol. Sci. Suppl. 1997, 37-39), and we here report the resolution, configurational assignment, and pharmacology of (S)- (6) and (R)- (7) Homo-AMPA. Using the {"}Ugi four-component condensation{"}, 3-(3-ethoxy-5-methylisoxazol-4-yl)propanal (10) was converted into the separable diastereomeric derivatives of 6 and 7, compounds 12 and 11, respectively. Deprotection of 12, in one or two steps, gave extensively racemized 6, which was converted in low yield into 6 (99.0{\%} ee) through several crystallizations. 6 (99.7{\%} ee) and 7 (99.9{\%} ee) were finally obtained by preparative chiral HPLC. The configurational assignments of 6 and 7 were based on 1H NMR spectroscopic studies on 12 and 11, respectively, and circular dichroism studies on 6 and 7. Values of optical rotations using different solvents and the chiral HPLC elution order of 6 and 7 supported the results of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu1-7 were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu6 (EC50 = 58 +/- 11 microM) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3 microM). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu1-7, turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 microM).",
keywords = "Animals, CHO Cells, Chromatography, High Pressure Liquid, Cricetinae, Cyclic AMP, Excitatory Amino Acid Agonists, Hydrolysis, Magnetic Resonance Spectroscopy, Membrane Potentials, Phosphatidylinositols, Rats, Receptors, Metabotropic Glutamate, Recombinant Proteins, Stereoisomerism, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid",
author = "H Ahmadian and B Nielsen and Hans Br{\"a}uner-Osborne and Johansen, {T N} and Stensb{\o}l, {T B} and Sl{\o}k, {F A} and N Sekiyama and S Nakanishi and P Krogsgaard-Larsen and U Madsen",
year = "1997",
month = "10",
day = "24",
doi = "10.1021/jm9703597",
language = "English",
volume = "40",
pages = "3700--5",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",

}

RIS

TY - JOUR

T1 - (S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors

AU - Ahmadian, H

AU - Nielsen, B

AU - Bräuner-Osborne, Hans

AU - Johansen, T N

AU - Stensbøl, T B

AU - Sløk, F A

AU - Sekiyama, N

AU - Nakanishi, S

AU - Krogsgaard-Larsen, P

AU - Madsen, U

PY - 1997/10/24

Y1 - 1997/10/24

N2 - Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu6 subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist for the pharmacological characterization of mGlu6 (Trends Pharmacol. Sci. Suppl. 1997, 37-39), and we here report the resolution, configurational assignment, and pharmacology of (S)- (6) and (R)- (7) Homo-AMPA. Using the "Ugi four-component condensation", 3-(3-ethoxy-5-methylisoxazol-4-yl)propanal (10) was converted into the separable diastereomeric derivatives of 6 and 7, compounds 12 and 11, respectively. Deprotection of 12, in one or two steps, gave extensively racemized 6, which was converted in low yield into 6 (99.0% ee) through several crystallizations. 6 (99.7% ee) and 7 (99.9% ee) were finally obtained by preparative chiral HPLC. The configurational assignments of 6 and 7 were based on 1H NMR spectroscopic studies on 12 and 11, respectively, and circular dichroism studies on 6 and 7. Values of optical rotations using different solvents and the chiral HPLC elution order of 6 and 7 supported the results of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu1-7 were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu6 (EC50 = 58 +/- 11 microM) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3 microM). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu1-7, turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 microM).

AB - Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu6 subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist for the pharmacological characterization of mGlu6 (Trends Pharmacol. Sci. Suppl. 1997, 37-39), and we here report the resolution, configurational assignment, and pharmacology of (S)- (6) and (R)- (7) Homo-AMPA. Using the "Ugi four-component condensation", 3-(3-ethoxy-5-methylisoxazol-4-yl)propanal (10) was converted into the separable diastereomeric derivatives of 6 and 7, compounds 12 and 11, respectively. Deprotection of 12, in one or two steps, gave extensively racemized 6, which was converted in low yield into 6 (99.0% ee) through several crystallizations. 6 (99.7% ee) and 7 (99.9% ee) were finally obtained by preparative chiral HPLC. The configurational assignments of 6 and 7 were based on 1H NMR spectroscopic studies on 12 and 11, respectively, and circular dichroism studies on 6 and 7. Values of optical rotations using different solvents and the chiral HPLC elution order of 6 and 7 supported the results of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu1-7 were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu6 (EC50 = 58 +/- 11 microM) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3 microM). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu1-7, turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 microM).

KW - Animals

KW - CHO Cells

KW - Chromatography, High Pressure Liquid

KW - Cricetinae

KW - Cyclic AMP

KW - Excitatory Amino Acid Agonists

KW - Hydrolysis

KW - Magnetic Resonance Spectroscopy

KW - Membrane Potentials

KW - Phosphatidylinositols

KW - Rats

KW - Receptors, Metabotropic Glutamate

KW - Recombinant Proteins

KW - Stereoisomerism

KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

U2 - 10.1021/jm9703597

DO - 10.1021/jm9703597

M3 - Journal article

C2 - 9357538

VL - 40

SP - 3700

EP - 3705

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 22

ER -

ID: 45596291