Dibenzo[1,2,5]thiadiazepines are non-competitive GABAA receptor antagonists.
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.
División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica, San Luis Potosí 78216, Mexico. francisco.martinez@uaslp.mx
Juan F
JF
Ramírez-Martínez
Rodolfo
R
González-Chávez
Raquel
R
Guerrero-Alba
Paul E
PE
Reyes-Gutiérrez
Roberto
R
Martínez
Marcela
M
Miranda-Morales
Rosa
R
Espinosa-Luna
Marco M
MM
González-Chávez
Carlos
C
Barajas-López
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D059330:GABAergic Neurons / Q000187:drug effects*; D006168:Guinea Pigs; D020128:Inhibitory Concentration 50; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009197:Myenteric Plexus / Q000166:cytology; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D011963:Receptors, GABA-A / Q000378:metabolism; D013829:Thiadiazines / Q000138:chemical synthesis / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D013829:Thiadiazines; D005680:gamma-Aminobutyric Acid