Benzodiazepine site ligands with partial efficacy

The imidazobenzodiazepines bretazenil, imidazenil, and FG-8205 (Figure 10a) are high-affinity partial agonists for GABAA receptor subtypes that contain a1, a2, a3, and a5 subunits. These compounds are anxiolytic in animal models, with a greater separation between doses required for anxiolytic versus sedative effects than that observed for diazepam. Where studied, these compounds also show little evidence for tolerance to the anxiolytic effects, do not display withdrawal, and have a lower abuse potential than full BZ agonists in nonhuman primates. Bretazenil (Figure 10a) entered clinical studies in the mid-1980s and was efficacious in GAD and panic disorder,112 with a lower abuse potential than diazepam.113 However, bretazenil was sedative, with little evidence for separation between anxiolytic and sedative effects,114 and its clinical development was discontinued.

The b-carboline abecarnil (Figure 10a), has high affinity for a1-, a2-, a3-, and a5-subunit-containing GABAA receptors, and has shown partial agonist activity in some, but not all, studies. Some reported pronounced anxiolytic versus sedative and muscle relaxant activity,115 while others reported marked sedation.116 Abecarnil was evaluated in the clinic and shown to be superior to placebo, equivalent to a BZ comparator although these effects were not always significant. The compound produced drowsiness and was discontinued in the 1990s.

The pyrazolopyrimidine, ocinaplon (Figure 10a), has relatively low affinity for rat brain BZ binding sites, being a positive allosteric modulator of GABAA receptors exhibiting partial agonist activity at all subtypes, with EC50 values in the 3-10 mM range.117 In animal models, it produces anxiolytic activity equivalent to diazepam with reduced sedative and muscle relaxant effects. Ocinaplon had efficacy in GAD patients with 2 weeks of dosing, with a side effect profile equivalent to placebo117 and is currently in phase III development, although it is currently on hold due to liver toxicity.

The pyridobenzimidazole, RWJ-51204 (Figure 10a), has low nanomolar affinity for BZ binding sites with the characteristics of a partial agonist,116 although no data are available for its actions on discrete a-subunit-containing

Anxiety and Depression 101

Anxiety and Depression 101

Everything you ever wanted to know about. We have been discussing depression and anxiety and how different information that is out on the market only seems to target one particular cure for these two common conditions that seem to walk hand in hand.

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