Pharmacological characterization of homobaclofen on wild type and mutant GABA(B)1b receptors coexpressed with the GABA(B)2 receptor
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Pharmacological characterization of homobaclofen on wild type and mutant GABA(B)1b receptors coexpressed with the GABA(B)2 receptor. / Jensen, Anders A.; Madsen, Bo E.; Krogsgaard-Larsen, P; Bräuner-Osborne, H.
In: European Journal of Pharmacology, Vol. 417, No. 3, 2001, p. 177-80.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Pharmacological characterization of homobaclofen on wild type and mutant GABA(B)1b receptors coexpressed with the GABA(B)2 receptor
AU - Jensen, Anders A.
AU - Madsen, Bo E.
AU - Krogsgaard-Larsen, P
AU - Bräuner-Osborne, H
PY - 2001
Y1 - 2001
N2 - Homobaclofen (5-amino-3-(4-chlorophenyl) pentanoic acid) is a homologue of the classical GABA(B) receptor agonist baclofen. In a recent study, the two enantiomers of this compound were tested in a GABA(B) receptor selective [3H]gamma-aminobutyric acid ([3H]GABA) binding assay using rat brain homogenate and in an assay of electrically induced contractions of guinea pig ileum. The results from the two tissues did, however, not correlate very well, and in order to further investigate these discrepancies, we have pharmacologically characterized these enantiomers on recombinant wild type and mutant rat GABA(B)1b receptors coexpressed with rat GABA(B)2 receptors. The results from this study correlate nicely with the binding data from rat brain. (R)-Homobaclofen was shown to act like (R)-baclofen albeit with 20-fold less potency, and (S)-homobaclofen was inactive on the receptor. The discrepancies between the data obtained in this study and those from the guinea pig ileum model could be ascribed to differences in amino acid sequence or receptor splicing of GABA(B) receptors between the two species. Another explanation for the observation is the possible existence of a novel yet uncloned GABA(B) receptor in guinea pig ileum.
AB - Homobaclofen (5-amino-3-(4-chlorophenyl) pentanoic acid) is a homologue of the classical GABA(B) receptor agonist baclofen. In a recent study, the two enantiomers of this compound were tested in a GABA(B) receptor selective [3H]gamma-aminobutyric acid ([3H]GABA) binding assay using rat brain homogenate and in an assay of electrically induced contractions of guinea pig ileum. The results from the two tissues did, however, not correlate very well, and in order to further investigate these discrepancies, we have pharmacologically characterized these enantiomers on recombinant wild type and mutant rat GABA(B)1b receptors coexpressed with rat GABA(B)2 receptors. The results from this study correlate nicely with the binding data from rat brain. (R)-Homobaclofen was shown to act like (R)-baclofen albeit with 20-fold less potency, and (S)-homobaclofen was inactive on the receptor. The discrepancies between the data obtained in this study and those from the guinea pig ileum model could be ascribed to differences in amino acid sequence or receptor splicing of GABA(B) receptors between the two species. Another explanation for the observation is the possible existence of a novel yet uncloned GABA(B) receptor in guinea pig ileum.
KW - Animals
KW - Baclofen
KW - Cell Line
KW - Dose-Response Relationship, Drug
KW - GABA-B Receptor Agonists
KW - Guinea Pigs
KW - Humans
KW - Inositol Phosphates
KW - Mutation
KW - Rats
KW - Receptors, GABA-B
KW - Recombinant Proteins
KW - Species Specificity
KW - Stereoisomerism
KW - Structure-Activity Relationship
KW - gamma-Aminobutyric Acid
M3 - Journal article
C2 - 11334848
VL - 417
SP - 177
EP - 180
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
IS - 3
ER -
ID: 38485294