title: Pharmacological re-evaluation of a GABA(B) receptor antagonist CGP 47332A in rat brain.
abstract: In rat neocortical slices maintained in Mg(2+)-free Krebs medium, the gamma-aminobutyric acid (GABA(B)) receptor agonist baclofen concentration-dependently depressed the frequency of spontaneous discharges (EC(50)=12 microM). This was reversibly antagonised by (R, S)-3-amino-2-hydroxy-propyl-P-n-butyl-phosphinic acid (CGP 47332A) (25, 100, 300 microM) which produced rightwards shifts of the baclofen concentration-response curves (pA(2) value=4.8+/-0.1). In electrically stimulated slices preloaded with [3H]GABA, CGP 47332A increased its release (EC(150)=100 microM) through antagonism of GABA(B) autoreceptors. Although CGP 47332A was some six times weaker on GABA(B) auto- than on heteroreceptors, yet its congener lacking the beta-hydroxy substituent displays equal potency in both binding (IC(50)=38 microM) and GABA(B) autoreceptor functional studies (EC(150)=38 microM) as previously reported [Froestl, W., Mickel, S.J. , Von Sprecher, G., Diel, P.J., Hall, R.G., Maier, L., Strub, D., Melillo, V., Baumann, P.A., Bernasconi, R., Gentsch, C., Hauser, K., Jaekel, J., Karlsson, G., Klebs, K., Maitre, L., Marescaux, C., Pozza, M.F., Schmutz, M., Steinmann, M.W., Van Riezen, H., Vassout, A., Mondadori, C., Olpe, H.R., Waldmeier, P.C., Bittiger, H., Phosphinic acid analogues of GABA: 2. Selective, orally active GABA(B) antagonists. J. Med. Chem. 38 (1995) 3313-3331.].
authors.affiliation: Department of Anaesthesia and Intensive Care, The University of Adelaide, Adelaide, Australia. jong@medicine.adelaide.edu.au
authors.forename: J
authors.initials: J
authors.lastname: Ong
authors.forename: V
authors.initials: V
authors.lastname: Marino
authors.forename: D A
authors.initials: DA
authors.lastname: Parker
authors.forename: D I
authors.initials: DI
authors.lastname: Kerr
authors.forename: W
authors.initials: W
authors.lastname: Froestl
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects*; D004558:Electric Stimulation; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D010721:Phosphinic Acids / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C403320:CGP 47332A; D018755:GABA Agonists; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D010721:Phosphinic Acids; D001418:Baclofen