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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

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

Stine B Vogensen, Jeremy R Greenwood, Annemarie R Varming, Lotte Brehm, Darryl S Pickering, Birgitte Nielsen, Tommy Liljefors, Rasmus P Clausen, Tommy N Johansen, Povl Krogsgaard-Larsen

Org Biomol Chem. 2004 Jan 21;2(2):206-13.

PMID: 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP944937284	1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methoxy-methyl-amide		944937-28-4	Price

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