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1.
Bioorg Med Chem ; 16(5): 2617-26, 2008 Mar 01.
Article in English | MEDLINE | ID: mdl-18063372

ABSTRACT

This paper reports the synthesis and AMPA, Gly/NMDA, and KA receptor binding affinities of a new set of 1,9-disubstituted-8-chloro-pyrazolo[1,5-c]quinazoline-2-carboxylates 2-34. Binding data show that, in general, compounds 2-34 bind to the AMPA receptor with good affinity and selectivity. In particular, the obtained results indicate that the contemporary presence of a 1,2-dicarboxylic acid moiety and suitable benzo-substituents on the PQZ system is important to gain selective AMPA receptor antagonists. Moreover, this study shows that the presence of a 2-carboxybenzoylamino substituent at position-9 (compounds 33-34) is important for obtaining selective KA receptor antagonists. Some selected compounds were also tested for their functional antagonistic activity at both AMPA and NMDA receptor-ion channels.


Subject(s)
Pyrazoles/chemistry , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Receptors, Kainic Acid/antagonists & inhibitors , Receptors, Kainic Acid/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemical synthesis , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology , Molecular Structure , N-Methylaspartate/chemistry , Quinazolines/chemistry , Structure-Activity Relationship , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemistry
2.
J Med Chem ; 50(10): 2408-14, 2007 May 17.
Article in English | MEDLINE | ID: mdl-17455929

ABSTRACT

Replacement of the methyl group of the AMPA receptor agonist 2-amino-3-[3-hydroxy-5-(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-AMPA) with a benzyl group provided the first AMPA receptor agonist, compound 7, capable of discriminating GluR2-4 from GluR1 by its more than 10-fold preference for the former receptor subtypes. An X-ray crystallographic analysis of this new analogue in complex with the GluR2-S1S2J construct shows that accommodation of the benzyl group creates a previously unobserved pocket in the receptor, which may explain the remarkable pharmacological profile of compound 7.


Subject(s)
Receptors, AMPA/agonists , Tetrazoles/chemical synthesis , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/analogs & derivatives , Amino Acid Sequence , Animals , Binding Sites , Brain/metabolism , Cell Line , Crystallography, X-Ray , In Vitro Techniques , Insecta , Models, Molecular , Molecular Sequence Data , Patch-Clamp Techniques , Radioligand Assay , Rats , Receptors, AMPA/chemistry , Receptors, AMPA/physiology , Stereoisomerism , Structure-Activity Relationship , Synaptosomes/metabolism , Tetrazoles/chemistry , Tetrazoles/pharmacology , Xenopus laevis , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemical synthesis , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemistry , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
3.
Bioorg Med Chem ; 13(18): 5391-8, 2005 Sep 15.
Article in English | MEDLINE | ID: mdl-16043357

ABSTRACT

Two 3-(5-tetrazolylmethoxy) analogues, 1a and 1b, of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA receptor agonist, and (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring agonist, were synthesized. Compounds 1a and 1b were pharmacologically characterized in receptor binding assays, and electrophysiologically on homomeric AMPA receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these receptors. Both analogues proved to be antagonists at all AMPA receptor subtypes, showing potencies (Kb=38-161 microM) similar to that of the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) (Kb=43-76 microM). Furthermore, the AMOA analogue, 1a, blocked two kainic acid receptor subtypes (GluR5 and GluR6/KA2), showing sevenfold preference for GluR6/KA2 (Kb=19 microM). Unlike the iGluR antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid [(S)-ATPO], the corresponding tetrazolyl analogue, 1b, lacks kainic acid receptor effects. On the basis of docking to a crystal structure of the isolated extracellular ligand-binding core of the AMPA receptor subunit GluR2 and a homology model of the kainic acid receptor subunit GluR5, we were able to rationalize the observed structure-activity relationships.


Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Receptors, Glutamate/drug effects , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology , Animals , Cell Line , Computer Simulation , Electrophysiology , Excitatory Amino Acid Agonists/chemical synthesis , Excitatory Amino Acid Agonists/chemistry , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/chemistry , Isoxazoles/chemistry , Models, Molecular , Oocytes/drug effects , Oocytes/metabolism , Patch-Clamp Techniques , Propionates/chemistry , Rats , Receptors, Glutamate/genetics , Receptors, Glutamate/metabolism , Xenopus laevis , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/analogs & derivatives , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemical synthesis
4.
J Med Chem ; 48(9): 3438-42, 2005 May 05.
Article in English | MEDLINE | ID: mdl-15857151

ABSTRACT

The synthesis and pharmacological characterization of 1- and 2-alkyltetrazolyl analogues of (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid (2-Me-Tet-AMPA), a highly potent and selective agonist at AMPA receptors, are presented. A shorter and more convergent synthetic route than previously described, employing a new method for introducing the amino acid moiety, was developed for these derivatives. The 2-substituted isomers were selective agonists, and their activity correlated inversely with the size of the substituent. Structural explanations of the structure-activity relationship are provided.


Subject(s)
Receptors, AMPA/agonists , Receptors, AMPA/metabolism , Tetrazoles/chemical synthesis , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/analogs & derivatives , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemical synthesis , Animals , Brain/metabolism , In Vitro Techniques , Models, Molecular , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity Relationship , Synaptosomes/metabolism , Tetrazoles/pharmacology , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
5.
Chirality ; 16(7): 452-66, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15236343

ABSTRACT

We have previously used homologation of (S)-glutamic acid (Glu) and Glu analogs as an approach to the design of selective ligands for different subtypes of Glu receptors. (RS)-2-Amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), which is an isoxazole homolog of Glu, is a very potent agonist at the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) subgroup of Glu receptors and a moderately potent ligand for the kainic acid (KA) subgroup of Glu receptors. The enantiomers of ACPA were previously obtained by chiral HPLC resolution. Prompted by pharmacological interest in ACPA, we have now prepared the (S)- and (R)-enantiomers of ACPA by stereocontrolled syntheses using (1R,2R,5R)- and (1S,2S,5S)-2-hydroxy-3-pinanone, respectively, as chiral auxiliaries. Furthermore, the 5-ethyl analog of ACPA, Ethyl-ACPA, was synthesized, and (S)- and (R)-Ethyl-ACPA were also prepared using this method. The absolute configurations of (S)- and (R)-ACPA were established by X-ray crystallographic analysis of a protected (1S,2S,5S)-2-hydroxy-3-pinanone imine derivative of (R)-ACPA. The absolute stereochemistry of (S)- and (R)-Ethyl-ACPA was assigned on the basis of a comparison of their properties with those of the enantiomers of ACPA, employing elution order on chiral HPLC columns, as well as circular dichroism (CD) spectroscopy in combination with time-dependent density functional theory. The structural and electronic basis for the Cotton effect observed for such analogs is examined. The lower homolog of ACPA, (RS)-2-amino-2-(3-carboxy-5-methyl-4-isoxazolyl)acetic acid (1), which is a Glu analog, was also synthesized. Affinities and neuroexcitatory effects were determined using rat brain membranes and cortical wedges, respectively, at native AMPA, KA, and N-methyl-D-aspartic acid (NMDA) receptors. The molecular pharmacology of (S)- and (R)-ACPA and (S)- and (R)-Ethyl-ACPA was evaluated at homomeric cloned subtypes of AMPA receptors (iGluR1o,3o,4o) and of KA receptors (iGluR5,6), expressed in Xenopus laevis oocytes. The cloned receptors mGluR1alpha, mGluR2, and mGluR4a, expressed in CHO cell lines, were used to study the effects of the five compounds at metabotropic Glu receptors. In accordance with ligand-receptor complexes known from X-ray crystallography, the conformationally restricted Glu analog 1 was inactive at all Glu receptors studied, and the R-forms of ACPA and Ethyl-ACPA were very weak or inactive at these receptors. At AMPA receptor subtypes, (S)-ACPA and (S)-Ethyl-ACPA showed equally potent agonist effects at iGluR1o and iGluR3o, whereas (S)-Ethyl-ACPA was 6-fold more potent than (S)-ACPA at iGluR4o. (S)-ACPA and (S)-Ethyl-ACPA were approximately an order of magnitude less potent at iGluR5 than at AMPA receptor subtypes, and neither compound showed detectable effects at iGluR6. The binding mode of (S)-Ethyl-ACPA at iGluR2 was examined by docking to the (S)-ACPA-iGluR2 complex.


Subject(s)
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemical synthesis , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology , Animals , CHO Cells , Chromatography, High Pressure Liquid , Circular Dichroism , Cricetinae , Crystallography, X-Ray , Electrophysiology , Glutamic Acid/metabolism , Hydrogen Bonding , Inhibitory Concentration 50 , Molecular Conformation , Ovum , Rats , Receptors, Glutamate/genetics , Receptors, Glutamate/metabolism , Second Messenger Systems/drug effects , Stereoisomerism , Xenopus , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/analogs & derivatives , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemistry
6.
Org Biomol Chem ; 2(2): 206-13, 2004 Jan 21.
Article in English | MEDLINE | ID: mdl-14737644

ABSTRACT

(RS)-3-Hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA)(), which is a conformationally constrained cyclised analogue of AMPA has previously been described as causing glutamate receptor mediated excitations of spontaneously firing cat spinal interneurons in a similar fashion to AMPA. We have now prepared the enantiomers of through chiral chromatographic resolution of (RS)-3-(carboxymethoxy)-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid () followed by a stereoconservative hydrolysis resulting in the enantiomers of with high enantiomeric excess (% ee [greater-than-or-equal] 99). The absolute configurations indicated by an X-ray analysis of (-)- monohydrate were confirmed by comparing observed and ab initio calculated electronic circular dichroism spectra and by stereoconservative synthesis of (S)- from (S)-AMPA, the pharmacologically active form of AMPA. The pharmacological effects at native and cloned (GluR1-4) AMPA receptors were shown to reside exclusively with (R)-(+)-, in striking contrast to the usual stereoselectivity trend among AMPA receptor agonists. The reasons for this anomalous behaviour became clear upon docking both enantiomers of to the agonist binding site of GluR2.


Subject(s)
2-Amino-5-phosphonovalerate/analogs & derivatives , Isoxazoles/chemistry , Isoxazoles/metabolism , Receptors, AMPA/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/analogs & derivatives , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism , 2-Amino-5-phosphonovalerate/chemistry , 2-Amino-5-phosphonovalerate/metabolism , Animals , Chromatography, High Pressure Liquid/methods , Circular Dichroism/methods , Crystallography, X-Ray , Cyclization , Isoxazoles/chemical synthesis , Models, Molecular , Molecular Conformation , Radioligand Assay , Rats , Receptors, AMPA/chemistry , Receptors, Kainic Acid/chemistry , Receptors, Kainic Acid/metabolism , Stereoisomerism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemical synthesis
7.
J Med Chem ; 41(14): 2513-23, 1998 Jul 02.
Article in English | MEDLINE | ID: mdl-9651156

ABSTRACT

We have previously shown that (S)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(S)-APPA, 2] is a weak agonist at (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors, specifically activated by (S)-AMPA (1), whereas (S)-2-amino-3-[3-hydroxy-5-(2-pyridyl)-4-isoxazolyl]propionic acid [(S)-2-Py-AMPA, 5] and (RS)-2-amino-3-[3-hydroxy-5-(2-thiazolyl)-4-isoxazolyl]propionic acid (4) are potent AMPA agonists. On the other hand, (R)-APPA (3) and (R)-2-Py-AMPA (6) have been shown to be weak AMPA antagonists. We now report the synthesis of 2-Py-AMPA (7a) and the isomeric compounds 3-Py-AMPA (7b) and 4-Py-AMPA (7c) as well as the 7a analogues, (RS)-2-amino-3-[3-hydroxy-5-(6-methyl-2-pyridyl)-4-isoxazolyl]p ropion ic acid (7d) and (RS)-2-amino-3-[3-hydroxy-5-(2-quinolinyl)-4-isoxazolyl]propionic acid (7e). Furthermore, (RS)-2-amino-3-[3-hydroxy-5-(2-furyl)-4-isoxazolyl]propionic acid (2-Fu-AMPA, 7f) and its 5-bromo-2-furyl derivative (7g) were synthesized, and (S)-2-Fu-AMPA (8) and (R)-2-Fu-AMPA (9) were prepared by semipreparative chiral HPLC resolution of 7f. HPLC analyses and circular dichroism spectroscopy indicated the absolute stereochemistry of 8 and 9 to be S and R, respectively. This was confirmed by an X-ray crystallographic analysis of 9.HCl. In receptor binding (IC50 values) and rat cortical wedge electrophysiological (EC50 values) studies, 7c (IC50 = 5.5 +/- 0.6 microM; EC50 = 96 +/- 5 microM) was shown to be markedly weaker than 7a (IC50 = 0.57 +/- 0.16 microM; EC50 = 7.4 +/- 0.2 microM) as an AMPA agonist, whereas 7b,d,e were inactive. The very potent AMPA agonist effect of 7f (IC50 = 0.15 +/- 0.03 microM; EC50 = 1.7 +/- 0. 2 microM) was shown to reside exclusively in 8 (IC50 = 0.11 +/- 0.01 microM; EC50 = 0.71 +/- 0.11 microM), whereas 9 did not interact significantly with AMPA receptors, either as an agonist or as an antagonist. 8 was shown to be photochemically active and is a potential photoaffinity label for the recognition site of the AMPA receptors. Compound 7g turned out to be a very weak AMPA receptor agonist (IC50 = 12 +/- 0.7 microM; EC50 = 160 +/- 15 microM). None of these new compounds showed detectable effects at N-methyl-d-aspartic acid (NMDA) or kainic acid receptors in vitro. The present studies have emphasized that the presence of a heteroatom in the 2-position of the heteroaryl 5-substituent greatly facilitates AMPA receptor agonist activity.


Subject(s)
Excitatory Amino Acid Agonists/chemical synthesis , Furans/chemical synthesis , Isoxazoles/chemical synthesis , Receptors, AMPA/agonists , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemical synthesis , Animals , Brain/drug effects , Brain/metabolism , Brain/physiology , Chromatography, High Pressure Liquid , Circular Dichroism , Crystallography, X-Ray , Electrophysiology , Excitatory Amino Acid Agonists/chemistry , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , In Vitro Techniques , Photoaffinity Labels/chemical synthesis , Photoaffinity Labels/chemistry , Photoaffinity Labels/pharmacology , Photochemistry , Rats , Receptors, AMPA/antagonists & inhibitors , Stereoisomerism , Structure-Activity Relationship , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/analogs & derivatives , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemistry , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
8.
J Med Chem ; 40(18): 2831-42, 1997 Aug 29.
Article in English | MEDLINE | ID: mdl-9288165

ABSTRACT

A number of 3-isoxazolol bioisosteres, 7a-i, of (S)-glutamic acid (Glu), in which the methyl group of (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 1) was replaced by different 5-membered heterocyclic rings, were synthesized. Comparative in vitro pharmacological studies on this series of AMPA analogues were performed using receptor binding assays (IC50 values) and the electrophysiological rat cortical slice model (EC50 values). None of these compounds showed detectable affinity for the N-methyl-D-aspartic acid subtype of Glu receptors. Some of the compounds were weak inhibitors of [3H]kainic acid binding. The inhibitory effects on [3H]AMPA binding and agonist potencies at AMPA receptors of 7a-i were strictly dependent on the structure, electrostatic potential, and methyl substitution of the heterocyclic 5-substituent. Thus, while 7a (IC50 = 0.094 microM; EC50 = 2.3 microM) was approximately equipotent with AMPA (IC50 = 0.023 microM; EC50 = 5.4 microM), (RS)-2-amino-3-[3-hydroxy-5-(1H-imidazol-2-yl)isoxazol-4-yl]propio nic acid (7b) (IC50 = 48 microM; EC50 = 550 microM) was some 2 orders of magnitude weaker than AMPA, and (RS)-2-amino-3-[3-hydroxy-5-(1-methyl-1H-imidazol-2-yl)-isoxazol-4 -yl] propionic acid (7c) (IC50 > 100 microM; EC50 > 1000 microM) was inactive. Furthermore, (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (7i) (IC50 = 0.030 microM; EC50 = 0.92 microM) was more potent than AMPA, whereas its N-1 methyl isomer, (RS)-2-amino-3-[3-hydroxy-5-(1-methyl-1H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (7h) (IC50 = 54 microM; EC50 > 1000 microM) was inactive as an AMPA agonist. A quantitative structure-activity relationship (QSAR) analysis revealed a positive correlation between receptor affinity, electrostatic potential near the nitrogen atom at the "ortho" position of the heterocyclic 5-substituent, and the rotational energy barrier around the bond connecting the two rings. We envisage that a hydrogen bond between the protonated amino group and an ortho-positioned heteroatom of the ring substituent at the 5-position stabilize receptor-active conformations of these AMPA analogues.


Subject(s)
Cerebral Cortex/physiology , Corpus Callosum/physiology , Isoxazoles/chemical synthesis , Isoxazoles/pharmacology , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/analogs & derivatives , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemical synthesis , Animals , Binding, Competitive , Cerebral Cortex/drug effects , Corpus Callosum/drug effects , Electrophysiology , Evoked Potentials/drug effects , In Vitro Techniques , Isoxazoles/chemistry , Kainic Acid/metabolism , Kinetics , Models, Molecular , Molecular Conformation , Molecular Structure , Potentiometry , Rats , Receptors, AMPA/drug effects , Receptors, AMPA/metabolism , Receptors, Kainic Acid/drug effects , Receptors, Kainic Acid/metabolism , Structure-Activity Relationship , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemistry , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
9.
J Med Chem ; 39(16): 3188-94, 1996 Aug 02.
Article in English | MEDLINE | ID: mdl-8759641

ABSTRACT

The homologous series of acidic amino acids, ranging from aspartic acid (1) to 2-aminosuberic acid (5), and the corresponding series of 3-isoxazolol bioisosteres of these amino acids, ranging from (RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid (AMAA, 6) to (RS)-2-amino-6-(3-hydroxy-5-methylisoxazol-4-yl)hexanoic acid (10), were tested as ligands for metabotropic excitatory amino acid receptors (mGlu1 alpha, mGlu2, mGlu4a, and mGlu6). Whereas AMAA (6) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propinoic acid (AMPA, 7) are potent and highly selective agonists at N-methyl-D-aspartic acid (NMDA) and AMPA receptors, respectively, the higher homologue of AMPA (7), (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (homo-AMPA, 8), is inactive at ionotropic excitatory amino acid receptors. Homo-AMPA (8), which is a 3-isoxazolol bioisostere of 2-aminoadipic acid (3), was, however, shown to be a specific and rather potent agonist at mGlu6, approximately 4 times weaker than the nonselective excitatory amino acid receptor agonist (S)-glutamic acid. 2-Aminoadipic acid (3), which shows a complex excitatory amino acid synaptic pharmacology, was an agonist at mGlu6 as well as mGlu2. AMPA (7) and the higher homologue of homo-AMPA (8), (RS)-2-amino-5-(3-hydroxy-5-methylisoxazol-4-yl)pentanoic acid (9), showed relatively weak agonist effects at mGlu6. It is concluded that homo-AMPA (8) is likely to be a useful tool for studies of the pharmacology and physiological role of mGlu6. We describe a new versatile synthesis of this homologue of AMPA and the synthesis of compound 10.


Subject(s)
Excitatory Amino Acid Agonists/chemical synthesis , Excitatory Amino Acid Agonists/pharmacology , Receptors, Metabotropic Glutamate/agonists , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/analogs & derivatives , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , CHO Cells , Cricetinae , Dose-Response Relationship, Drug , Excitatory Amino Acid Agonists/chemistry , Excitatory Amino Acid Agonists/metabolism , Magnetic Resonance Spectroscopy , Molecular Structure , N-Methylaspartate/pharmacology , Receptors, Metabotropic Glutamate/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemical synthesis , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/chemistry , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
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