GABA AGONISTS AND UPTAKE INHIBITORS - SYNTHESIS, ABSOLUTE STEREOCHEMISTRY, AND ENANTIOSELECTIVITY OF (R)-(-)-HOMO-BETA-PROLINE AND (S)-(+)-HOMO-BETA-PROLINE

The cyclic analogue of 4-aminobutyric acid (GABA), 3-pyrrolidineacetic acid (homo-β-proline), is a potent agonist at GABAAreceptors, it interacts effectively with GABA-uptake mechanisms, and it is a moderately potent inhibitor of GABABreceptor binding. (R)-(-)-(10) and (S)-(+)-homo-β-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-β-proline (15), respectively. The absolute stereochemistry of 10 and 15 was established on the basis of an X-ray analysis of compound 5. The enantiomers 10 and 15 were shown to bind to GABAAand GABABreceptor sites with opposite stereoselectivity. Thus, (β)-homo-β-proline (10) proved to be more than 1 order of magnitude more potent than the S enantiomer (15) as an inhibitor of GABAAreceptor binding, whereas the GABABreceptor affinity of homo-β-proline was shown to reside exclusively in (S)-homo-β-proline (15). In contrast to the stereoselective receptor affinities of 10 and 15, these enantiomers were approximately equieffective as inhibitors of synaptosomal GABA uptake. © 1990, American Chemical Society. All rights reserved.