Comparative potencies of CGP 47654A and CGP 46165A as GABA B receptor antagonists 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=6.1 μM). This was reversibly antagonised by 3-aminopropyl-(1,1-difluoro- n-butyl)-phosphinic acid (25, 100, 500 μM) (CGP 47654A) and 3-aminopropyl- P-(α-hydroxybenzyl)-phosphinic acid (CGP 46165A) (50, 100, 400 μM) which produced rightwards shifts of the baclofen concentration–response curves, with respective pA 2 values of 4.9±0.2 and 4.6±0.15. Although relatively potent on GABA B heteroreceptors studied here, CGP 47654A and CGP 46165A were 5 and 50 times weaker, respectively, as GABA B autoreceptor antagonists [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., 1995. Phosphinic acid analogues of GABA. 2. Selective, orally active GABA B antagonists. J. Med. Chem. 38: 3313–3331.], representing potentially useful ligands for differentiating GABA B hetero- and autoreceptors.