División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica, San Luis Potosí 78216, Mexico.
Molecules. 2013 Jan 11;18(1):894-913. doi: 10.3390/molecules18010894.
A new process for obtaining dibenzo[c,f][1,2,5]thiadiazepines (DBTDs) and their effects on GABA(A) receptors of guinea pig myenteric neurons are described. Synthesis of DBTD derivatives began with two commercial aromatic compounds. An azide group was obtained after two sequential reactions, and the central ring was closed via a nitrene to obtain the tricyclic sulfonamides (DBTDs). Whole-cell recordings showed that DBTDs application did not affect the holding current but inhibited the currents induced by GABA (I(GABA)), which are mediated by GABA(A) receptors. These DBTDs effects reached their maximum 3 min after application and were: (i) reversible, (ii) concentration-dependent (with a rank order of potency of 2c = 2d > 2b), (iii) mediated by a non-competitive antagonism, and (iv) only observed when applied extracellularly. Picrotoxin (which binds in the channel mouth) and DBTDs effects were not modified when both substances were simultaneous applied. Our results indicate that DBTD acted on the extracellular domain of GABA(A) channels but independent of the picrotoxin, benzodiazepine, and GABA binding sites. DBTDs used here could be the initial model for synthesizing new GABA(A) receptor inhibitors with a potential to be used as antidotes for positive modulators of these receptors or to induce experimental epilepsy.
描述了一种获得二苯并[c,f][1,2,5]噻二嗪（DBTDs）的新方法及其对豚鼠肌间神经元 GABA(A)受体的影响。DBTD 衍生物的合成都始于两种商业芳香化合物。经过两步连续反应得到叠氮基团，然后通过氮宾环合得到三环磺酰胺（DBTDs）。全细胞记录显示，DBTDs 的应用并不影响保持电流，但抑制了由 GABA（I(GABA)）诱导的电流，这些电流是由 GABA(A)受体介导的。这些 DBTDs 的作用在应用后 3 分钟达到最大值，具有以下特点：（i）可逆，（ii）浓度依赖性（效力顺序为 2c = 2d > 2b），（iii）通过非竞争性拮抗介导，（iv）仅在细胞外应用时观察到。当同时应用普罗布考（结合在通道口）和 DBTDs 时，它们的作用没有改变。我们的结果表明，DBTD 作用于 GABA(A)通道的细胞外结构域，但与普罗布考、苯二氮䓬和 GABA 结合位点无关。这里使用的 DBTDs 可以作为合成新的 GABA(A)受体抑制剂的起始模型，具有作为这些受体的正调节剂的解毒剂或诱导实验性癫痫的潜力。
