title: N,N'-dicyclohexylsulfamide and N,N'-diphenethylsulfamide are anticonvulsant sulfamides with affinity for the benzodiazepine binding site of the GABA(A) receptor and anxiolytic activity in mice.
abstract: A set of sulfamides designed, synthesized and evaluated against maximal electroshock seizure (MES) and pentilenetetrazol (PTZ) tests with promising results, were tested for their affinity for the benzodiazepine binding site of the GABA(A) receptor. The most active compounds, N,N'-dicyclohexylsulfamide (7) and N,N'-diphenethylsulfamide (10), competitively inhibited the binding of [(3)H]-flunitrazepam to the benzodiazepine binding site with K(i)±SEM values of 27.7±4.5μM (n=3) and 6.0±1.2μM (n=3), respectively. The behavioral actions of these sulfamides, i.p. administered in mice, were examined in the plus-maze, hole-board and locomotor activity assays. Compound 7 exhibited anxiolytic-like effects in mice evidenced by a significant increase of the parameters measured in the hole-board test (at 1 and 3mg/kg) and the plus-maze assay (at 1 and 3mg/kg). Compound 10 evidenced anxiolytic activity in the plus-maze and the hole-board tests at 1mg/kg. Locomotor activity of mice was not modified by compound 7 or 10 at the doses tested. Flumazenil, a non selective benzodiazepine binding site antagonist, was able to completely reverse the anxiolytic-like effects of these sulfamides, proving that the GABA(A) receptor is implicated in this action. Anxiety represents a major problem for people with epilepsy. The use of anxiolytic and anticonvulsant sulfamides would be beneficial to individuals who suffer from both disorders.
authors: Instituto de Química y Fisicoquímica Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (C1113AAD), Buenos Aires, Argentina. criswasowski@qb.ffyb.uba.ar
authors: Cristina
authors: C
authors: Wasowski
authors: Luciana
authors: L
authors: Gavernet
authors: Ivana A
authors: IA
authors: Barrios
authors: Maria L
authors: ML
authors: Villalba
authors: Valentina
authors: V
authors: Pastore
authors: Gisela
authors: G
authors: Samaja
authors: Andrea
authors: A
authors: Enrique
authors: Luis E
authors: LE
authors: Bruno-Blanch
authors: Mariel
authors: M
authors: Marder
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D000927:Anticonvulsants / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D001569:Benzodiazepines / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D005445:Flunitrazepam / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D011963:Receptors, GABA-A; D013449:Sulfonamides; D001569:Benzodiazepines; D005445:Flunitrazepam