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Tytuł pozycji:

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

Tytuł:
(S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors.
Autorzy:
Ahmadian H; Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Nielsen B
Bräuner-Osborne H
Johansen TN
Stensbøl TB
Sløk FA
Sekiyama N
Nakanishi S
Krogsgaard-Larsen P
Madsen U
Źródło:
Journal of medicinal chemistry [J Med Chem] 1997 Oct 24; Vol. 40 (22), pp. 3700-5.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
MeSH Terms:
Excitatory Amino Acid Agonists/*pharmacology
Receptors, Metabotropic Glutamate/*agonists
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/*analogs & derivatives
Animals ; CHO Cells ; Chromatography, High Pressure Liquid ; Cricetinae ; Cyclic AMP/biosynthesis ; Excitatory Amino Acid Agonists/chemistry ; Hydrolysis ; In Vitro Techniques ; Magnetic Resonance Spectroscopy ; Membrane Potentials/drug effects ; Phosphatidylinositols/metabolism ; Rats ; Receptors, Metabotropic Glutamate/classification ; Recombinant Proteins/agonists ; Recombinant Proteins/classification ; Stereoisomerism ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemistry ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
Substance Nomenclature:
0 (2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid)
0 (Excitatory Amino Acid Agonists)
0 (Phosphatidylinositols)
0 (Receptors, Metabotropic Glutamate)
0 (Recombinant Proteins)
77521-29-0 (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid)
E0399OZS9N (Cyclic AMP)
Entry Date(s):
Date Created: 19971114 Date Completed: 19971211 Latest Revision: 20141120
Update Code:
20240104
DOI:
10.1021/jm9703597
PMID:
9357538
Czasopismo naukowe
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).

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