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-prolin...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1990-01, Vol.33 (1), p.71-77
Main Authors: Nielsen, Lone, Brehm, Lotte, Krogsgaard-Larsen, Povl
Format: Article
Language:English
Subjects:
Animals
Brain - ultrastructure
Chemical Phenomena
Chemistry
Condensed matter: structure, mechanical and thermal properties
Exact sciences and technology
Female
GABA Antagonists
gamma-Aminobutyric Acid - metabolism
Heterocyclic compounds
Heterocyclic compounds with only one n hetero atom and condensed derivatives
Hydrogen Bonding
Male
Molecular Conformation
Molecular Structure
Neurotransmitter Uptake Inhibitors - chemical synthesis
Neurotransmitter Uptake Inhibitors - metabolism
Neurotransmitter Uptake Inhibitors - pharmacology
Nipecotic Acids - chemical synthesis
Nipecotic Acids - metabolism
Nipecotic Acids - pharmacology
Organic chemistry
Organic compounds
Physics
Preparations and properties
Proline - analogs & derivatives
Rats
Rats, Inbred Strains
Receptors, GABA-A - metabolism
Stereoisomerism
Structure of solids and liquids
crystallography
Structure of specific crystalline solids
Structure-Activity Relationship
Synaptic Membranes - metabolism
Synaptosomes - drug effects
Synaptosomes - metabolism
X-Ray Diffraction
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Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00163a012