Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Pharmacol Biochem Behav. 2010 Jun;95(4):383-9. doi: 10.1016/j.pbb.2010.02.016. Epub 2010 Mar 19.
Recent evidence suggests that alpha1-containing GABA(A) receptors mediate the sedative, amnestic, and to some extent the anticonvulsant actions of non-selective benzodiazepine (BZ) receptor ligands, such as diazepam (DZ). Anxiolytic and in part, anticonvulsant actions of BZ ligands are mediated by alpha2-, alpha3-, and alpha5-containing GABA(A) receptors. This has resulted in increasing interest in developing BZ ligands with selective actions at GABA(A) receptors, including alpha2-, alpha3-, and alpha5-subunits, but devoid of efficacy at alpha1-containing receptors. To refine their spectrum of pharmacological actions, efforts are being made to minimize unwanted effects such as sedation, amnesia, and tolerance liabilities. A prototype for such BZ ligands is imidazenil (IMD), an imidazo-benzodiazepine carboxylic acid derivative that elicits potent anticonvulsant and anxiolytic actions at doses virtually devoid of sedative, cardio-respiratory depressant and amnestic effects, and anticonvulsant tolerance liability. To define the pharmacological profile of IMD and its derivatives, we compared the anticonflict (anxiolytic), anti-proconflict (antipanic), anti-bicuculline (BIC), and maximal electroshock seizure (MES) effects, and the suppression of locomotor activity by imidazo-benzodiazepine carboxylic acid derivatives to those of DZ and bretazenil (BTZ). We report here that IMD and one of its derivatives (RO 25-2775) possess dose-dependent anticonflict, anti-proconflict, and anti-BIC actions but failed to suppress locomotor activity. Like DZ, the other IMD derivatives (enazenil, RO 25-2776, and RO 25-2847) not only elicit dose-dependent anticonflict, anti-proconflict, anti-BIC, anti-MES effects but also suppress locomotor activity. In contrast, none of the IMD derivatives studied shows any similarity to BTZ, which elicits anticonflict, anti-proconflict actions and suppresses locomotor activity but is virtually inactive against BIC-induced tonic-clonic convulsions.
最近的证据表明，含有α1 亚基的 GABA(A) 受体介导非选择性苯二氮䓬（BZ）受体配体（如地西泮[DZ]）的镇静、失忆和在某种程度上的抗惊厥作用。BZ 配体的抗焦虑和部分抗惊厥作用是通过含有α2、α3 和α5 亚基的 GABA(A) 受体介导的。这导致人们越来越关注开发对 GABA(A) 受体具有选择性作用的 BZ 配体，包括α2、α3 和α5 亚基，但对含有α1 亚基的受体无效。为了完善其药理作用谱，人们正在努力最大限度地减少镇静、失忆和耐药性等不良反应。此类 BZ 配体的原型是咪唑并苯二氮䓬羧酸衍生物依美沙仑（IMD），它在几乎没有镇静、心肺抑制和失忆作用以及抗惊厥耐药性的剂量下，引发强烈的抗惊厥和抗焦虑作用。为了确定 IMD 及其衍生物的药理学特征，我们比较了其抗冲突（抗焦虑）、抗促冲突（抗惊恐）、抗双氢古柯碱（BIC）和最大电休克发作（MES）作用，以及咪唑并苯二氮䓬羧酸衍生物对运动活性的抑制作用与 DZ 和倍他唑仑（BTZ）的作用。我们在此报告，IMD 及其一种衍生物（RO 25-2775）具有剂量依赖性的抗冲突、抗促冲突和抗 BIC 作用，但未能抑制运动活性。与 DZ 一样，IMD 的其他衍生物（依美沙仑、RO 25-2776 和 RO 25-2847）不仅引发剂量依赖性的抗冲突、抗促冲突、抗 BIC、抗 MES 作用，还抑制运动活性。相比之下，研究的 IMD 衍生物均与 BTZ 无相似性，BTZ 引发抗冲突、抗促冲突作用并抑制运动活性，但对 BIC 诱导的强直-阵挛性惊厥几乎无效。
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