IMIDAZENIL - A NEW PARTIAL POSITIVE ALLOSTERIC MODULATOR OF GAMMA-AMINOBUTYRIC-ACID (GABA) ACTION AT GABA(A) RECEPTORS

Positive allosteric modulators of gamma-aminobutyric acid (GABA)A rece ptors, 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 GABA(A) re ceptors; 2) selective allosteric modulators (i.e., diazepam) that act with high potency and high efficacy at selected GABA(A) receptors; and 3) partial allosteric modulators (i.e., bretazenil) that act with hig h potency but low efficacy at many GABA(A) receptors. Imidazenil, an i midazobenzodiazepine carboxamide, has been characterized as a novel re presentative of the partial allosteric modulator class. When tested on a broad spectrum (native and recombinant) of GABA(A) receptors, imida zenil positively modulates the GABA-elicited Cl- currents with a 4- to 5-fold higher potency but an efficacy (30-50%) lower than that of dia zepam, and it antagonizes the effects of the latter drug. Imidazenil i n vitro (K(i) = 5 x 10(-10) M) and in vivo (ID50 = 0.2 mumol/kg i.v.) displaces [H-3]flumazenil from its brain binding sites and in vivo it possesses a marked anticonflict profile in the rat Vogel conflict-puni shment test and is 1 0 times more potent than bretazenil and 1 00 time s more potent than diazepam or alprazolam in antagonizing bicuculline- and pentylenetetrazol-induced seizures. Unlike diazepam and alprazola m, which induce sedation and ataxia and potentiate the effects of etha nol 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 1 00% occupancy of brain flumazenil binding sites. Furthermore, when administered with di azepam, imidazenil blocks in a dose-related fashion the sedative, atax ic effects of this drug and thus acts on these unwanted responses as a n antagonist (i.e., like flumazenil). In all tests, imidazenil has the pharmacological profile of a partial allosteric modulator, but is mor e potent than bretazenil, has a longer biological half-life and, in ro dents, is virtually unable to cause sedation, ataxia or to potentiate ethanol toxicity.