GABA agonists and uptake inhibitors. Synthesis, absolute stereochemistry, and enantioselectivity of (R)-(-)- and (S)-(+)-homo-.beta.-proline

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Abstract
The cyclic analogue of 4-aminobutyric acid (GABA), 3-pyrrolidineacetic acid (homo-.beta.-proline), is a potent agonist at GABAA receptors, it interacts effectively with GABA-uptake mechanisms, and it is a moderately potent inhibitor of GABAB receptor binding. (R)-(.sbd.-)- (10) and (S)-(+)-homo-.beta.-proline (15) were synthesized via methyl (3S)-1-[(R)-1-phenylethyl]-5-oxo-3-pyrrolidinecarboxylate (5) and its 3R diastereomer (4), respectively. The mixture 3 consisting of 4 and 5 was synthesized via addition-cyclization reactions between (R)-1-phenylethylamine and itaconic acid (1). The diastereomers 5 and 4, which were separated chromatographically, were converted into (R)- (10) and (S)-homo-.beta.-proline (15), respectively. The absolute stereochemistry of 10 and 5 was established on the basis of and X-ray analysis of compound 5. The enantiomers 10 and 15 were shown to bind to GABAA and GABAB receptor sites with opposite stereoselectivity. Thus, (R)-homo-.beta.-proline (10) proved to be more than 1 order of magnitude more potent than the enantiomer (15) as an inhibitor of GABAA receptor binding, whereas the GABAB receptor affinity of homo-.beta.-proline was shown to reside exclusively in (S)-homo-.beta.-proline (15). In contrast to the stereoselective receptor affinities of 10 and 15, these enantiomers were approximately equieffective as inhibitors of synaptosomal GABA uptake.