Maksay G, Molnár P, Gruber L
Department of Molecular Pharmacology, Hungarian Academy of Sciences, Budapest.
Eur J Pharmacol. 1994 Dec 15;288(1):61-8. doi: 10.1016/0922-4106(94)90010-8.
The effects of pentylenetetrazol and bicyclic gamma-butyrolactones of similar stereostructures were studied on the convulsant and benzodiazepine binding sites and chloride ionophore activity of the gamma-aminobutyric acid (GABAA) receptor-complex. Bicyclic gamma-butyrolactones displayed millimolar IC50 values and low stereoselectivities on [35S]t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites in synaptosomal membranes of rat forebrains. Ring saturation of bicyclic gamma-butyrolactones decreased their IC50 values by one order of magnitude. The IC50 values of saturated bicyclic gamma-butyrolactones and pentylenetetrazol were increased by GABA versus its antagonist R 5135 (3 alpha-hydroxy-16-imino-5 beta,17-aza-androstan-11-one). A bicyclic gamma-butyrolactone and pentylenetetrazol accelerated the dissociation of [35S]TBPS, displaced [3H]flumazenil binding in two phases and blocked the muscimol-elicited chloride currents in patch-clamped cortical neurones in culture in a similar manner. These similar effects on binding and ionophore function support their common modes of action on the GABAA receptor-ionophore complex.
研究了戊四氮和具有相似立体结构的双环γ-丁内酯对γ-氨基丁酸（GABAA）受体复合物的惊厥位点、苯二氮䓬结合位点及氯离子载体活性的影响。双环γ-丁内酯在[35S]叔丁基双环磷硫代酸盐（TBPS）与大鼠前脑突触体膜惊厥位点的结合上显示出毫摩尔级的半数抑制浓度（IC50）值和低立体选择性。双环γ-丁内酯的环饱和使其IC50值降低了一个数量级。与拮抗剂R 5135（3α-羟基-16-亚氨基-5β,17-氮杂雄甾-11-酮）相比，GABA可使饱和双环γ-丁内酯和戊四氮的IC50值升高。一种双环γ-丁内酯和戊四氮加速了[35S]TBPS的解离，分两个阶段取代[3H]氟马西尼结合，并以类似方式阻断了培养的膜片钳皮质神经元中蝇蕈醇引发的氯离子电流。这些对结合和离子载体功能的相似影响支持了它们对GABAA受体-离子载体复合物的共同作用模式。
