Comparative potencies of CGP 47654A and CGP 46165A as GABA(B) receptor antagonists in rat brain

In rat neocortical slices maintained in Mg2+-free Krebs medium, the gamma-a minobutyric acid (GABA(B)) receptor agonist baclofen concentration-dependen tly depressed the frequency of spontaneous discharges (EC50 = 6.1 mu M) Thi s was reversibly antagonised by 3-aminopropyl-(1,1-difluoro-n-butyl)-phosph inic acid (25, 100, 500 mu M) (CGP 47654A) and 3-aminopropyl-P-(alpha-hydro xybenzyl)-phosphinic acid (CGP 46165A) (50, 100, 400 mu M) which produced r ightwards shifts of the baclofen concentration-response curves. with respec tive pA(2) values of 4.9 +/- 0.2 and 4.6 +/- 0.15. Although relatively pote nt on GABA(B) heteroreceptors studied here, CGP 47654A and CGP 46165A were 5 and 50 times weaker, respectively, as GABA(B) autoreceptor antagonists [F roestl, W., Mickel, S.J., Von Sprecher, G., Dial, P.J., Hall, R.G., Mater, L.. Strub, D., Melillo, V., Baumann, P.A., Bernasconi, R., Gentsch, C., Hau ser, K., Jaekel, J., Karlsson, G., Klebs, K., Maitre, L., Marescaux, C., Po zza, M.F,, Schmutz, M., Steinmann, M.W., Van Riezen, H., Vassout, A., Monda dori, 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 differe ntiating GABA(B) hetero- and autoreceptors. (C) 1999 Elsevier Science B.V. All rights reserved.