Juan Ramirez-Martinez - Dibenzo[1,2,5]thiadiazepines are Non-Competitive GABAA Receptor Antagonists

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      Publication Details (including relevant citation   information):

        MYENTERIC NEURONSANTIDEPRESSANTPHARMACOLOGYDERIVATIVESINHIBITORS; GABAA   RECEPTORS;   SYNTHESIS 

      Molecules  18,   894-913

      Abstract:

        A new process for obtaining dibenzo[c,f][1,2,5]thiadiazepines   (DBTDs) and their effects on GABAA 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 (IGABA), which are mediated   by GABAA 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 GABAA channels but independent of the picrotoxin,   benzodiazepine, and GABA binding sites. DBTDs used here could be   the initial model for synthesizing new GABAA receptor   inhibitors with a potential to be used as antidotes for positive   modulators of these receptors or to induce experimental   epilepsy.

      Address (URL): http://www.mdpi.com/1420-3049/18/1/894