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 γ-aminobutyric acid (GABA B) receptor agonist baclofen concentration-dependently depressed the frequency of spontaneous discharges (EC 50=12 μM). This was reversibly antagonised by ( R, S)-3-amino-2-hydroxy-propyl- P- n-butyl-phosphinic acid (CGP 47332A) (25, 100, 300 μM) which produced rightwards shifts of the baclofen concentration–response curves (p A 2 value=4.8±0.1). In electrically stimulated slices preloaded with [ 3H]GABA, CGP 47332A increased its release (EC 150=100 μM) 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 β-hydroxy substituent displays equal potency in both binding (IC 50=38 μM) and GABA B autoreceptor functional studies (EC 150=38 μM) 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.].