title: Pharmacological characterization of homobaclofen on wild type and mutant GABA(B)1b receptors coexpressed with the GABA(B)2 receptor.
abstract: 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.
authors.affiliation: NeuroScience PharmaBiotec Research Centre, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
authors.forename: A A
authors.initials: AA
authors.lastname: Jensen
authors.forename: B E
authors.initials: BE
authors.lastname: Madsen
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: H
authors.initials: H
authors.lastname: Bräuner-Osborne
mesh_terms: D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D058786:GABA-B Receptor Agonists; D006168:Guinea Pigs; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D051381:Rats; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000494:pharmacology
chemical_list: C430877:5-amino-3-(4-chlophenyl)pentanoic acid; D058786:GABA-B Receptor Agonists; D007295:Inositol Phosphates; D018080:Receptors, GABA-B; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D001418:Baclofen