Anxiolytic drugs, determination

The choice of drug as hypnotic and anxiolytic is determined by pharmacokinetic properties (see before, and Table 19.8). 

Further, the removal of benzodiazepine sensitivity in a selective a subunit in a mouse using the gene knockin technique has established that the al subunit plays a major role in the sedative and amnesiac effects of benzodiazepines, part of the anticonvulsant effect and little of the anxiolytic effect the latter effects are more importantly mediated by the a2 subunit [5, 6], The 0 subunit selectivity for the drugs loreclezole (an anxiolytic) and etomidate (an anesthetic) allowed determination that a single residue in the M2 domain could account for this selectivity (02 = 03 >01). When a mouse knockin selectively removed the etomidate sensitivity of the 02 subunit, the animals showed reduced sensitivity to sedative effects of etomidate but no reduction of the true anesthetic effects. In contrast, mutation of the 03 subunit to negate etomidate sensitivity of that subunit alone resulted in a mouse with no sensitivity to the anesthesia produced by etomidate. This proved that the GABA receptor is the target of at least this one anesthetic (etomidate) and, furthermore, that the specific locations in the brain of 03 subunits are important for anesthetic action, while the... 

The synthesis of 1,5-benzodiazepinediones was undertaken to determine the parameters of structural modifications that will retain and possibly improve the anxiolytic profile. Two such drugs have been developed outside the United States clobazepam and triflubazepam. Replacement of benzo portion of BZDs with heteroaromatics was also accomplished. Ripazepam represents a pyrazole congener. It was equipotent to diazepam yet showed a striking absence of sedation in animal tests. In clinical tests, however, sedation was present, even though it was less. 

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