GABA B antagonists: Resolution, absolute stereochemistry, and pharmacology of (R)‐ and (S)‐phaclofen

Phaclofen, which is the phosphonic acid analogue of the GABA B agonist (RS)‐3‐(4‐chlorophenyl)‐4‐aminobutyric acid (baclofen), is a GABA B antagonist. As part of our studies on the structural requirements for activation and blockade of GABA B 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 [ 3 H]‐(R)‐baclofen to GABA B receptor sites on rat cerebellar membranes (IC 50 = 76 ± 13 μ M ), whereas (+)‐(S)‐phaclofen was inactive in this binding assay (IC 50 > 1000 μ M ). (−)‐(R)‐Phaclofen (200 μ M ) was equipotent with (RS)‐phaclofen (400 μ M ) in antagonizing the action of baclofen in rat cerebral cortical slices, while (+)‐(S)‐phaclofen (200 μ M ) was inactive. The structural similarity of the agonist (R)‐baclofen and the antagonist (−)‐(R)‐phaclofen suggests that these ligands interact with the GABA B 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.