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

Abstract

(RS)-3-Hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA) (1), 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 1 through chiral chromatographic resolution of (RS)-3-(carboxymethoxy)-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (2) followed by a stereoconservative hydrolysis resulting in the enantiomers of 1 with high enantiomeric excess (% ee ≥ 99). The absolute configurations indicated by an X-ray analysis of (−)-1 monohydrate were confirmed by comparing observed and ab initio calculated electronic circular dichroism spectra and by stereoconservative synthesis of (S)-1 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)-(+)-1, 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 1 to the agonist binding site of GluR2.