Abstract
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.