GABAB antagonists: resolution, absolute stereochemistry, and pharmacology of (R)- and (S)-phaclofen

TY - JOUR

T1 - GABAB antagonists

T2 - resolution, absolute stereochemistry, and pharmacology of (R)- and (S)-phaclofen

AU - Frydenvang, Karla Andrea

AU - Hansen, J J

AU - Krogsgaard-Larsen, P

AU - Mitrovic, A

AU - Tran, H

AU - Drew, C A

AU - Johnston, G A

PY - 1994

Y1 - 1994

N2 - 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.

AB - 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.

KW - Animals

KW - Baclofen

KW - Cerebral Cortex

KW - Chromatography, High Pressure Liquid

KW - Crystallography, X-Ray

KW - GABA Antagonists

KW - GABA-B Receptor Antagonists

KW - Models, Molecular

KW - Molecular Conformation

KW - Molecular Structure

KW - Rats

KW - Stereoisomerism

KW - Structure-Activity Relationship

U2 - 10.1002/chir.530060712

DO - 10.1002/chir.530060712

M3 - Journal article

C2 - 7986672

SN - 0899-0042

VL - 6

SP - 583

EP - 589

JO - Chirality

JF - Chirality

IS - 7

ER -