Morpholin-2-yl-phosphinic acids are potent GABA(B) receptor antagonists inrat brain

The pharmacological properties of morpholin-2-yl-phosphinic acids were eval uated on GABA, receptors. In rat neocortical slices maintained in Mg2+-free Krebs medium, baclofen, a GABA, receptor agonist, produced a concentration -dependent depression of the frequency of spontaneous discharges with an EC 50 of 14 +/- 5.5 mu M, which was antagonised reversibly by the morpholin-2- yl-phosphinic derivatives. The order of potency was 3-{(3S,6R)-6-[(cyclohex ylmethyl)hydroxyphosphinoylmethyl]-morpholin-3-yl}benzoic acid (CGP 76290A) (pA(2) = 7.1 +/- 0.05) > its enantiomer 3-{(3R,6S)-6-[(cyclohexylmethyl)hy droxyphosphinoylmethyl]-morpholin-3-yl}benzoic acid (CGP 76291A) (pA(2) = 6 .8 +/- 0.1) > cyclohexylmethyl-[(2R',SS')-5-(3-nitrophenyl)-morpholin-2-ylm ethyl]phosphinic acid (CGP 71978) (pA(2) = 6.5 +/- 0.05) > cyclohexylmethyl -[(2R,SS)-5-phenyl-morpholin-2-ylmethyl]phosphinic acid(CGP 71980) (pA(2) = 6.3 +/- 0.15) > its enantiomer cyclohexylmethyl-[(2S,SR)-5-phenyl-morpholi n-2-ylmethyl]phosphinic acid (CGP 71979) (pA(2) = 5.8 +/- 0.1). An open cha in analogue of CGP 76290A, CGP 56999A (3-{1(R)-[(3-cyclohexylmethyl-hydroxy phosphinoyl)-2(S)-hydroxypropyl-amino]-ethyl}benzoic acid lithium salt) gav e a pA(2) of 6.6 +/- 0.2. In GABA(B) receptor binding assays, CGP 71982 (th e racemic mixture of CGP 76290A and CGP 76291A), CGP 76290A, CGP 76291A, CG P 71978, CGP 71980 and CGP 71979 had IC50 values against [H-3]CGP 27492 bin ding of 8, 1.85, 69, 124, 326 and 1460 nM, respectively. In electrically-ev oked [3H]GABA release from rat cortical slices, CGP 71982, CGP 71978, CGP 7 1980 and its enantiomer CGP 71979, antagonised GABA(B) autoreceptors with E C150 values of 2.5, 33, 181 and 474 nM, respectively. These compounds form a novel class of potent GABA(B) receptor antagonists. (C) 1998 Elsevier Sci ence B.V. All rights reserved.