Pharmacological re-evaluation of a GABA(B) receptor antagonist CGP 47332A in rat brain

In rat neocortical slices maintained in Mg2+-free Krebs medium, the gamma-a minobutyric acid (GABA,) receptor agonist baclofen concentration-dependentl y depressed the frequency of spontaneous discharges (EC50 = 12 mu M) This w as reversibly antagonised by (R,S)-3-amino-2-hydroxy-propyl-P-n-butyl-phosp hinic acid (CGP 47332A) (25, 100, 300 mu M) which produced rightwards shift s of the baclofen concentration-response curves (pA(2) value = 4.8 +/- 0.1) . In electrically stimulated slices preloaded with [H-3]GABA, CGP 47332A in creased its release (EC150 = 100 mu M) through antagonism of GABA(B) autore ceptors. Although CGP 47332A was some six times weaker on GABA(B) auto- tha n on heteroreceptors, yet its congener lacking the beta-hydroxy substituent displays equal potency in both binding (IC50 = 38 mu M) and GABA, autorece ptor functional studies (EC150 = 38 mu M) as previously reported [Froestl, W., Mickel, S.J., Von Sprecher, G., Diel, P.J., Hall, R.G., Maier, L., Stru b, 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 G ABA: 2. Selective, orally active GABA(B) antagonists. J.,Med. Chem. 38 (199 5) 3313-3331.]. (C) 1999 Elsevier Science B.V. All rights reserved.