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GABA B antagonists: Resolution, absolute stereochemistry, and pharmacology of (R)‐ and (S)‐phaclofen
Author(s) -
Frydenvang Karla,
Hansen Jan J.,
KrogsgaardLarsen Povl,
Mitrovic Ann,
Tran Hue,
Drew Colleen A.,
Johnston Graham A. R.
Publication year - 1994
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530060712
Subject(s) - chemistry , baclofen , agonist , antagonist , gabab receptor , stereochemistry , pharmacology , receptor , biochemistry , biology
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.