A stereochemical anomaly: the cyclised (R)-AMPA analogue (R)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid [(R)-5-HPCA] resembles (S)-AMPA at glutamate receptors.
(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.
Vogensen
Stine B
SB
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Greenwood
Jeremy R
JR
Varming
Annemarie R
AR
Brehm
Lotte
L
Pickering
Darryl S
DS
Nielsen
Birgitte
B
Liljefors
Tommy
T
Clausen
Rasmus P
RP
Johansen
Tommy N
TN
Krogsgaard-Larsen
Povl
P
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002942:Circular Dichroism / Q000379:methods; D018360:Crystallography, X-Ray; D003500:Cyclization; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*
D015763:2-Amino-5-phosphonovalerate; D007555:Isoxazoles; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C069052:CGP 39653