Positive allosteric modulators of
gamma-aminobutyric acid (
GABA)A receptors, including
benzodiazepines and congeners, can be classified into three categories: 1) full allosteric modulators (i.e.,
triazolam and
alprazolam) that act with high potency and efficacy at many GABAA receptors; 2) selective allosteric modulators (i.e.,
diazepam) that act with high potency and high efficacy at selected GABAA receptors; and 3) partial allosteric modulators (i.e.,
bretazenil) that act with high potency but low efficacy at many GABAA receptors.
Imidazenil, an imidazobenzodiazepine carboxamide, has been characterized as a novel representative of the partial allosteric modulator class. When tested on a broad spectrum (native and recombinant) of GABAA receptors,
imidazenil positively modulates the
GABA-elicited Cl- currents with a 4- to 5-fold higher potency but an efficacy (30-50%) lower than that of
diazepam, and it antagonizes the effects of the latter drug.
Imidazenil in vitro (Ki = 5 x 10(-10) M) and in vivo (ID50 = 0.2 mumol/kg i.v.) displaces [3H]
flumazenil from its brain binding sites and in vivo it possesses a marked anticonflict profile in the rat Vogel conflict-punishment test and is 10 times more potent than
bretazenil and 100 times more potent than
diazepam or
alprazolam in antagonizing
bicuculline- and
pentylenetetrazol-induced
seizures. Unlike
diazepam and
alprazolam, which induce sedation and
ataxia and potentiate the effects of
ethanol and
thiopental at doses similar to those that produce anticonflict effects and occupy 50% of brain
flumazenil binding sites,
imidazenil does not produce
ataxia or sedation in rats nor does it potentiate the effects of
ethanol or
thiopental in doses 30- to 50-fold higher than those required for the anticonflict effect and for 100% occupancy of brain
flumazenil binding sites. Furthermore, when administered with
diazepam,
imidazenil blocks in a dose-related fashion the
sedative, ataxic effects of this drug and thus acts on these unwanted responses as an antagonist (i.e., like
flumazenil). In all tests,
imidazenil has the pharmacological profile of a partial allosteric modulator, but is more potent than
bretazenil, has a longer biological half-life and, in rodents, is virtually unable to cause sedation,
ataxia or to potentiate
ethanol toxicity.