GABA agonists and uptake inhibitors. Synthesis, absolute stereochemistry, and enantioselectivity of (R)-(-)- and (S)-(+)-homo-beta-proline.
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)-(-)- (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 15 was established on the basis of an 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 S 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.
Nielsen
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Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen.
Brehm
L
L
Krogsgaard-Larsen
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D000818:Animals; D001921:Brain / Q000648:ultrastructure; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D018756:GABA Antagonists; D006860:Hydrogen Bonding; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014961:X-Ray Diffraction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018756:GABA Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; C030278:nipecotic acid; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline