Ong J, Kerr D I, Bittiger H, Waldmeier P C, Baumann P A, Cooke N G, Mickel S J, Froestl W
Department of Anaesthesia and Intensive Care, The University of Adelaide, South Australia, Australia.
Eur J Pharmacol. 1998 Nov 27;362(1):27-34. doi: 10.1016/s0014-2999(98)00747-x.
The pharmacological properties of morpholin-2-yl-phosphinic acids were evaluated on GABA(B) receptors. In rat neocortical slices maintained in Mg2+-free Krebs medium, baclofen, a GABA(B) receptor agonist, produced a concentration-dependent depression of the frequency of spontaneous discharges with an EC50 of 14 +/- 5.5 microM, which was antagonised reversibly by the morpholin-2-yl-phosphinic derivatives. The order of potency was 3-[(3S,6R)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl- morpholin-3-yl]benzoic acid (CGP 76290A) (pA2 = 7.1 +/- 0.05) > its enantiomer 3-[(3R,6S)-6-[(cyclohexylmethyl)hydroxyphosphinoylmethyl]-++ +morpholin-3-yl]benzoic acid (CGP 76291A) (pA2 = 6.8 +/- 0.1) > cyclohexylmethyl-[(2R',5S')-5-(3-nitrophenyl)-morpholin-2-++ +ylmethyl]phosphinic acid (CGP 71978) (pA2 = 6.5 +/- 0.05) > cyclohexylmethyl-[(2R,5S)-5-phenyl-morpholin-2-ylmethyl++ +]phosphinic acid (CGP 71980) (pA2 = 6.3 +/- 0.15) > its enantiomer cyclohexylmethyl-[(2S,5R)-5-phenyl-morpholin-2-ylmethyl++ +]phosphinic acid (CGP 71979) (pA2 = 5.8 +/- 0.1). An open chain analogue of CGP 76290A, CGP 56999A (3-[1(R)-[(3-cyclohexylmethyl-hydroxyphosphinoyl)-2(S)-hydro xypropyl-amino]-ethyl]benzoic acid lithium salt) gave a pA2 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 IC50 values against [3H]CGP 27492 binding of 8, 1.85, 69, 124, 326 and 1460 nM, respectively. In electrically-evoked [3H]GABA release from rat cortical slices, CGP 71982, CGP 71978, CGP 71980 and its enantiomer CGP 71979, antagonised GABA(B) autoreceptors with EC150 values of 2.5, 33, 181 and 474 nM, respectively. These compounds form a novel class of potent GABA(B) receptor antagonists.
对吗啉 - 2 - 基膦酸的药理学特性进行了GABA(B)受体评估。在无镁的Krebs培养基中维持的大鼠新皮质切片中，GABA(B)受体激动剂巴氯芬产生浓度依赖性的自发放电频率抑制，EC50为14±5.5微摩尔，其被吗啉 - 2 - 基膦酸衍生物可逆性拮抗。效力顺序为3 - [(3S,6R)-6 - [(环己基甲基)羟基膦酰基甲基 - 吗啉 - 3 - 基]苯甲酸（CGP 76290A）（pA2 = 7.1±0.05）>其对映体3 - [(3R,6S)-6 - [(环己基甲基)羟基膦酰基甲基] - 吗啉 - 3 - 基]苯甲酸（CGP 76291A）（pA2 = 6.8±0.1）>环己基甲基 - [(2R',5S') - 5 - (3 - 硝基苯基) - 吗啉 - 2 - 基甲基]膦酸（CGP 71978）（pA2 = 6.5±0.05）>环己基甲基 - [(2R,5S) - 5 - 苯基 - 吗啉 - 2 - 基甲基]膦酸（CGP 71980）（pA2 = 6.3±0.15）>其对映体环己基甲基 - [(2S,5R) - 5 - 苯基 - 吗啉 - 2 - 基甲基]膦酸（CGP 71979）（pA2 = 5.8±0.1）。CGP 76290A的开链类似物CGP 56999A（3 - [1(R)-[(3 - 环己基甲基 - 羟基膦酰基)-2(S)-羟基丙基 - 氨基] - 乙基]苯甲酸锂盐）的pA2为6.6±0.2。在GABA(B)受体结合试验中，CGP 71982（CGP 76290A和CGP 76291A的外消旋混合物）、CGP 76290A、CGP 76291A、CGP 71978、CGP 71980和CGP 71979对[3H]CGP 27492结合的IC50值分别为8、1.85、69、124、326和1460纳摩尔。在大鼠皮质切片电诱发的[3H]GABA释放中，CGP 71982、CGP 71978、CGP 71980及其对映体CGP 71979分别以2.5、33、181和474纳摩尔的EC150值拮抗GABA(B)自身受体。这些化合物构成了一类新型的强效GABA(B)受体拮抗剂。
