Giusti P, Ducić I, Puia G, Arban R, Walser A, Guidotti A, Costa E
Fidia-Georgetown Institute for the Neurosciences, Georgetown University Medical School, Washington, District of Columbia.
J Pharmacol Exp Ther. 1993 Aug;266(2):1018-28.
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.
γ-氨基丁酸（GABA）A受体的正变构调节剂，包括苯二氮䓬类及其类似物，可分为三类：1）完全变构调节剂（即三唑仑和阿普唑仑），它们对许多GABAA受体具有高效能和高效力；2）选择性变构调节剂（即地西泮），它们对选定的GABAA受体具有高效能和高效力；3）部分变构调节剂（即布瑞氮䓬），它们对许多GABAA受体具有高效能但低效力。咪唑安定，一种咪唑并苯二氮䓬甲酰胺，已被表征为部分变构调节剂类别的新型代表。当在广泛的（天然和重组）GABAA受体上进行测试时，咪唑安定能正向调节GABA诱导的Cl-电流，其效能比地西泮高4至5倍，但效力（30 - 50%）低于地西泮，并且它能拮抗后一种药物的作用。咪唑安定在体外（Ki = 5×10⁻¹⁰ M）和体内（ID50 = 0.2 μmol/kg静脉注射）能将[³H]氟马西尼从其脑结合位点置换出来，并且在体内，它在大鼠Vogel冲突 - 惩罚试验中具有显著的抗冲突特征，在拮抗荷包牡丹碱和戊四氮诱导的癫痫发作方面比布瑞氮䓬强10倍，比地西泮或阿普唑仑强100倍。与地西泮和阿普唑仑不同，地西泮和阿普唑仑在产生抗冲突效应和占据50%脑氟马西尼结合位点的剂量下会诱导镇静和共济失调，并增强乙醇和硫喷妥钠的作用，而咪唑安定在大鼠中不会产生共济失调或镇静作用，在比抗冲突效应所需剂量和100%占据脑氟马西尼结合位点所需剂量高30至50倍的剂量下也不会增强乙醇或硫喷妥钠的作用。此外，当与地西泮一起给药时，咪唑安定以剂量相关的方式阻断该药物的镇静、共济失调作用，因此作为拮抗剂作用于这些不良反应（即像氟马西尼一样）。在所有测试中，咪唑安定具有部分变构调节剂的药理学特征，但比布瑞氮䓬更有效，具有更长的生物半衰期，并且在啮齿动物中几乎不会引起镇静、共济失调或增强乙醇毒性。
