title: GABAB antagonists: resolution, absolute stereochemistry, and pharmacology of (R)- and (S)-phaclofen.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen.
authors.forename: K
authors.initials: K
authors.lastname: Frydenvang
authors.forename: J J
authors.initials: JJ
authors.lastname: Hansen
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: A
authors.initials: A
authors.lastname: Mitrovic
authors.forename: H
authors.initials: H
authors.lastname: Tran
authors.forename: C A
authors.initials: CA
authors.lastname: Drew
authors.forename: G A
authors.initials: GA
authors.lastname: Johnston
mesh_terms: D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray / Q000379:methods; D018756:GABA Antagonists / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; C052329:phaclofen; D001418:Baclofen