Ciclotizolam

The effects of 1,4-diazepines with two annelated heterocycles [brotizolam (WE 941), ciclotizolam (WE 973) and WE 1008] on gamma-aminobutyric acid (GABA)-stimulated chloride influx into rat brain membrane vesicles were examined. Brotizolam enhanced GABA (30 microM)-stimulated 36Cl- influx (146.1% of control), while ciclotizolam and WE 1008 showed only a small enhancement (119.3% and 119.1%, respectively) of GABA-stimulated 36Cl- uptake. Brotizolam resulted in a left shift of the GABA dose response curve at lower concentrations of GABA (10 microM), while at higher concentrations of GABA (1 mM), brotizolam caused a reduction of the maximal response. The enhancement of GABA-stimulated 36Cl- uptake by brotizolam (0.1 microM) was antagonized by Ro 15-1788. At higher concentration of GABA (300 microM), brotizolam inhibited GABA-stimulated 36Cl- uptake in a dose dependent manner and Ro15-1788 failed to antagonize this effect. These results suggest that 1) brotizolam produces an enhancement of GABA (30 microM)-stimulated chloride influx through the benzodiazepine receptor. 2) brotizolam inhibition of GABA (300 microM)-stimulated chloride influx involves an additional mechanism, and 3) the sedative-hypnotic action of brotizolam may be related to its high efficacy at the benzodiazepine/GABA-gated chloride channel.

Title compound I is monoclinic, space group P2₁/c, with a 12.385(2), b 8.674(1), c 14.335(2) Å, and β 104.91(1)°; d_c = 1.695 for Z = 4.Title compound II is monoclinic, space group P2₁/c, with a 8.140(1), b 14.982(7), c 16.095(9) Å, and β 99.09(3)°; d_c = 1.583 for Z = 4.The final R's = 0.045 and 0.028 for I and II, resp.At. coordinates are given.The angle between the mean planes of the Ph and thieno rings is 88.8 and 88.3° for I and II, resp.The triazolo ring is planar in both compoundsThe 7-membered ring adopts a cycloheptatrienelike boat conformation with bow and stern angles of 55.4 and 29.2° in I and 55.3 and 32.9° in II.