Morpholin-2-yl-phosphinic acids are potent GABA B receptor antagonists in rat brain

Abstract

The pharmacological properties of morpholin-2-yl-phosphinic acids were evaluated on GABA B receptors. In rat neocortical slices maintained in Mg 2+-free Krebs medium, baclofen, a GABA B receptor agonist, produced a concentration-dependent depression of the frequency of spontaneous discharges with an EC 50 of 14±5.5 μM, which was antagonised reversibly by the morpholin-2-yl-phosphinic derivatives. The order of potency was 3-{(3 S,6 R)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-morpholin-3-yl}benzoic acid (CGP 76290A) (p A 2=7.1±0.05)>its enantiomer 3-{(3 R,6 S)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-morpholin-3-yl}benzoic acid (CGP 76291A) (p A 2=6.8±0.1)>cyclohexylmethyl-[(2 R′,5 S′)-5-(3-nitrophenyl)-morpholin-2-ylmethyl]phosphinic acid (CGP 71978) (p A 2=6.5±0.05)>cyclohexylmethyl-[(2 R,5 S)-5-phenyl-morpholin-2-ylmethyl]phosphinic acid (CGP 71980) (p A 2=6.3±0.15)>its enantiomer cyclohexylmethyl-[(2 S,5 R)-5-phenyl-morpholin-2-ylmethyl]phosphinic acid (CGP 71979) (p A 2=5.8±0.1). An open chain analogue of CGP 76290A, CGP 56999A (3-{1( R)-[(3-cyclohexylmethyl-hydroxyphosphinoyl)-2( S)-hydroxypropyl-amino]-ethyl}benzoic acid lithium salt) gave a p A 2 of 6.6±0.2. In GABA B receptor binding assays, CGP 71982 (the racemic mixture of CGP 76290A and CGP 76291A), CGP 76290A, CGP 76291A, CGP 71978, CGP 71980 and CGP 71979 had IC 50 values against [ 3 H ]CGP 27492 binding of 8, 1.85, 69, 124, 326 and 1460 nM, respectively. In electrically-evoked [ 3 H ]GABA release from rat cortical slices, CGP 71982, CGP 71978, CGP 71980 and its enantiomer CGP 71979, antagonised GABA B autoreceptors with EC 150 values of 2.5, 33, 181 and 474 nM, respectively. These compounds form a novel class of potent GABA B receptor antagonists.