THE ACTION OF NEW POTENT GABA(B) RECEPTOR ANTAGONISTS IN THE HEMISECTED SPINAL-CORD PREPARATION OF THE RAT

CGP 52432 (3-N-(3,4-dichlorobenzyl)aminopropyl-P-diethoxymethylphosphinic acid), CGP 54062 (3-N[1-(R,S)-(3,4-dichlorophenyl) ethyl]amino-2-(S)-hydroxypropyl-P-benzyl-phosphinic acid), CGP 54626 (3-N[[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2(S)-hydroxypropyl-P-cyclohexylmethylphosphinic acid) and CGP 55845 (3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-P-benzyl-phosphinic acid) are novel selective GABA(B) receptor antagonists. The apparent K(d) values for the complex formed between the GABA(B) receptor and these compounds were determined using the monosynaptic reflex in the hemisected rat spinal cord preparation in vitro. CGP 55845 was found to be the most potent GABA(B) receptor antagonist tested (apparent K(d) = 30 nM). On the same preparation 0.3 muM CGP 55845 was equipotent with 100 muM of CGP 35348 (P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid) for reversal of the depressant action of (R)-(-)-baclofen.