GABAB antagonists: resolution, absolute stereochemistry, and pharmacology of (R)- and (S)-phaclofen

Research output: Contribution to journalJournal articlepeer-review

Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral chromatographic techniques. The absolute stereochemistry of (-)-(R)-phaclofen was established by X-ray crystallographic analysis. (-)-(R)-Phaclofen was shown to inhibit the binding of [3H]-(R)-baclofen to GABAB receptor sites on rat cerebellar membranes (IC50 = 76 +/- 13 microM), whereas (+)-(S)-phaclofen was inactive in this binding assay (IC50 > 1000 microM). (-)-(R)-Phaclofen (200 microM) was equipotent with (RS)-phaclofen (400 microM) in antagonizing the action of baclofen in rat cerebral cortical slices, while (+)-(S)-phaclofen (200 microM) was inactive. The structural similarity of the agonist (R)-baclofen and the antagonist (-)-(R)-phaclofen suggests that these ligands interact with the GABAB receptor sites in a similar manner. Thus, it may be concluded that the different pharmacological effects of these compounds essentially result from the different spatial and proteolytic properties of their acid groups.
Original languageEnglish
Issue number7
Pages (from-to)583-9
Number of pages7
Publication statusPublished - 1994

    Research areas

  • Animals, Baclofen, Cerebral Cortex, Chromatography, High Pressure Liquid, Crystallography, X-Ray, GABA Antagonists, GABA-B Receptor Antagonists, Models, Molecular, Molecular Conformation, Molecular Structure, Rats, Stereoisomerism, Structure-Activity Relationship

ID: 40372640