GABAB antagonists: Resolution,absolute stereochemistry,and pharmacology of (R)- and (S)-phaclofen |
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Authors: | Karla Frydenvang Jan J. Hansen Povl Krogsgaard-Larsen Ann Mitrovic Hue Tran Colleen A. Drew Graham A. R. Johnston |
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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 μM), whereas (+)-(S)-phaclofen was inactive in this binding assay (IC50 > 1000 μM). (?)-(R)-Phaclofen (200 μM) was equipotent with (RS)-phaclofen (400 μM) in antagonizing the action of baclofen in rat cerebral cortical slices, while (+)-(S)-phaclofen (200 μM) 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. © 1994 Wiley-Liss, Inc. |
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Keywords: | chiral HPLC resolution absolute configuration X-ray analysis GABAB antagonist GABAB receptor affinity phaclofen |
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