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Molecules 2013, 18(1), 894-913;

Dibenzo[1,2,5]thiadiazepines Are Non-Competitive GABAA Receptor Antagonists

División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica, San Luis Potosí 78216, Mexico
Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí 78210, Mexico
Instituto de Química, Universidad Nacional Autónoma de México, Coyoacán 04510, Mexico
Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro 76230, Mexico
Authors to whom correspondence should be addressed.
Received: 14 December 2012 / Revised: 31 December 2012 / Accepted: 5 January 2013 / Published: 11 January 2013
(This article belongs to the Section Medicinal Chemistry)
PDF [371 KB, uploaded 18 June 2014]


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. View Full-Text
Keywords: dibenzothiadiazepines; GABAA receptor antagonists; patch clamp; neurochemistry; biological activity; enteric neurons; electrophysiology dibenzothiadiazepines; GABAA receptor antagonists; patch clamp; neurochemistry; biological activity; enteric neurons; electrophysiology

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Ramírez-Martínez, J.F.; González-Chávez, R.; Guerrero-Alba, R.; Reyes-Gutiérrez, P.E.; Martínez, R.; Miranda-Morales, M.; Espinosa-Luna, R.; González-Chávez, M.M.; Barajas-López, C. Dibenzo[1,2,5]thiadiazepines Are Non-Competitive GABAA Receptor Antagonists. Molecules 2013, 18, 894-913.

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