Ong J, Marino V, Parker D A, Kerr D I, Blythin D J
Department of Anaesthesia and Intensive Care, The University of Adelaide, South Australia, Australia.
Eur J Pharmacol. 1998 Nov 27;362(1):35-41. doi: 10.1016/s0014-2999(98)00723-7.
The pharmacological properties of (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch 50911) were evaluated on GABA(B) receptors in rat neocortical slices. The GABA(B) receptor agonist, baclofen, produced a concentration-dependent depression of the frequency of spontaneous discharges in slices maintained in Mg2+-free Krebs medium with an EC50 of 6 microM, reversibly antagonised by Sch 50911 (5, 10 and 25 microM) with an apparent pA2 of 6.0 +/- 0.1. The (-) enantiomer Sch 50910 (500 microM) and the racemic des-methyl analogue Sch 48588 (500 microM) were inactive. In slices preloaded with [3H]GABA, Sch 50911 antagonised GABA(B) autoreceptors, increasing the electrically-stimulated 3H overflow in a concentration-dependent manner, with an IC50 of 3 microM. The maximal effect (148 +/- 10.5%) was found at 10 microM, but at 50 microM the response was reduced to 67 +/- 19%. In contrast, evoked release was unaffected by Sch 50910 (100 microM) whilst Sch 48588 at 100 microM increased the overflow by 51.3 +/- 11.6%. In summary, Sch 50911 is a relatively potent antagonist of considerable potential in studies of GABA(B) receptor function.
对(+)-(S)-5,5-二甲基吗啉基-2-乙酸（Sch 50911）的药理学特性在大鼠新皮质切片中的γ-氨基丁酸B（GABA(B)）受体上进行了评估。GABA(B)受体激动剂巴氯芬在无镁的Krebs培养基中维持的切片中产生了浓度依赖性的自发放电频率抑制，其半数有效浓度（EC50）为6微摩尔，可被Sch 50911（5、10和25微摩尔）可逆性拮抗，其表观拮抗常数（pA2）为6.0±0.1。(-)对映体Sch 50910（500微摩尔）和消旋去甲基类似物Sch 48588（500微摩尔）无活性。在预先加载[3H]GABA的切片中，Sch 50911拮抗GABA(B)自身受体，以浓度依赖性方式增加电刺激的3H溢出，其半数抑制浓度（IC50）为3微摩尔。在10微摩尔时发现最大效应（148±10.5%），但在50微摩尔时反应降至67±19%。相比之下，Sch 50910（100微摩尔）对诱发释放无影响，而100微摩尔的Sch 48588使溢出增加51.3±11.6%。总之，Sch 50911是一种相对强效的拮抗剂，在GABA(B)受体功能研究中具有相当大的潜力。
