Ciclotizolam

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.

1,4-Diazepines with two annelated heterocycles ('hetrazepines') such as brotizolam (WE 941), WE 973 and WE 1008 bind with high affinities to benzodiazepine receptors in the central nervous system. Brotizolam has a pharmacologic spectrum of action similar to clinically useful benzodiazepines, while the closely related derivatives WE 973 and WE 1008 appear to lack hypnotic action. Unlike other benzodiazepine receptor ligands which share common pharmacologic properties with the benzodiazepines, the apparent affinities of WE 973 and WE 1008 are not increased significantly in the presence of GABA, even at an elevated incubation temperature. Furthermore, the apparent affinities of these compounds do not appear to be reduced as a result of increasing the incubation temperature. Brotizolam, like the benzodiazepines, facilitates GABAergic transmission in zona recitulata neurons of the substantia nigra. In contrast, at a dose which inhibits cell firing, WE 973 does not appear to significantly augment the inhibitory action of GABA in these cells. These observations suggest that the so-called 'GABA shift' may not be a valid means of distinguishing benzodiazepine-like compounds in vitro. Furthermore, these data suggest that facilitation of GABAergic transmission may be necessary for the hypnotic action of benzodiazepine receptor ligands, but not for the anticonflict or the anticonvulsant actions of such compounds.