GABAB antagonists: resolution, absolute stereochemistry, and pharmacology of (R)- and (S)-phaclofen
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GABAB antagonists : resolution, absolute stereochemistry, and pharmacology of (R)- and (S)-phaclofen. / Frydenvang, Karla Andrea; Hansen, J J; Krogsgaard-Larsen, P; Mitrovic, A; Tran, H; Drew, C A; Johnston, G A.
In: Chirality, Vol. 6, No. 7, 1994, p. 583-9.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 6
SP - 583
EP - 589
JO - Chirality
JF - Chirality
SN - 0899-0042
IS - 7
ER -
ID: 40372640