(S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors.
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).
Ahmadian
H
H
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Nielsen
B
B
Bräuner-Osborne
H
H
Johansen
T N
TN
Stensbøl
T B
TB
Sløk
F A
FA
Sekiyama
N
N
Nakanishi
S
S
Krogsgaard-Larsen
P
P
Madsen
U
U
D000818:Animals; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000494:pharmacology*; D006868:Hydrolysis; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008564:Membrane Potentials / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000145:classification; D011994:Recombinant Proteins / Q000819:agonists / Q000145:classification; D013237:Stereoisomerism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
C100921:2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid; D018690:Excitatory Amino Acid Agonists; D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000242:Cyclic AMP