ABSTRACT
Many substances modulate the function of ionotropic receptors for the major inhibitory transmitter in the brain, GABA, producing a range of much sought-after pharmacological actions. The most widely studied are the benzodiazepines, such as diazepam. Benzodiazepines modulate GABA receptors by two distinct and separable actions in the nanomolar and micromolar concentration ranges. The anxiolytic and sedative actions of benzodiazepines are mediated through the high-affinity (nanomolar) mechanism. Such actions are blocked by the silent allosteric modulator flumazenil.
Flavonoids are plant products that occur widely in many foods and beverages. Consumed in the diet, flavonoids readily get into the brain where they are known to produce a range of desired effects, e.g., the calming effects of green tea. Many flavonoids have flumazenil-sensitive anxiolytic and sedative actions as modulators of the activation of GABAA receptors. In addition, some flavonoids have flumazenil-insensitive anxiolytic and sedative actions on GABAA receptors that may be mediated through the low-affinity (micromolar) benzodiazepine sites. The low-affinity benzodiazepine sites might be more correctly described as flavonoid sites that modulate GABAA receptors. These sites can be selectively blocked by the flavonoid Fa173, which acts as a silent allosteric modulator. Originally described as “a new family of benzodiazepine receptor ligands,” flavonoids should be recognized as having their own distinctive actions on ionotropic GABA receptors.
