NEUROCHEMICAL AND BEHAVIORAL EFFECTS OF NOVEL 8-ACETYLENYL ANALOGS OF TRIAZOLAM

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。最近的研究集中在了解苯二氮卓类药物（BZ）行为效应背后的GABA-A受体机制。两个新开发的化合物ANX 3和ANX 4是镇静催眠药BZ三唑仑的8-乙炔基类似物。在人GABA-A受体中，ANX 3和ANX 4的总体疗效和效力特征与三唑仑相似;然而，在低浓度下，与ANX 3和三唑仑相比，ANX 4对含有α-1亚基的GABA-A受体的效力降低。我们评估了ANX 4的功能选择性导致与三唑仑和ANX 3不同的抗焦虑和镇静运动作用的程度。在恒河猴中评估了溶血样活性。在松鼠猴中评价了可观察到的行为效应，包括肌肉松弛、共济失调和俯卧姿势的测量。ANX 3，ANX 4和三唑仑诱导抗焦虑样作用，并在所有行为指标中具有可靠的作用。对产生所有行为的最低有效剂量的检查表明三唑仑的相对效力的等级顺序大于ANX 3大于ANX 4。虽然ANX 3在所有行为测量中的效力比三唑仑低约3倍，但ANX 4在产生共济失调和平卧姿势（30倍）方面的效力比肌肉松弛低，这可能反映了该化合物对α-lGABA-A受体的效力降低。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent research has focused on understanding the GABA-A receptor mechanisms underlying the behavioral effects of benzodiazepines (BZs). Two newly developed compounds, ANX3 and ANX4, are 8-acetylenyl analogs of the sedative-hypnotic BZ triazolam. In human GABA-A receptors, the overall efficacy and potency profiles of ANX3 and ANX4 resemble that of triazolam; however, at low concentrations ANX4 has reduced potency at the alpha-1 subunit-containing GABA-A receptor compared to both ANX3 and triazolam. We evaluated the extent to which ANX4's functional selectivity resulted in anxiolytic and sedative-motor effects that differed from triazolam and ANX3. Anxiolytic-like activity was assessed in rhesus monkeys. Observable behavioral effects were evaluated in squirrel monkeys and included measurement of muscle relaxation, ataxia, and procumbent posture. ANX3, ANX4 and triazolam induced anxiolytic-like effects and had reliable effects in all behavioral measures. Examination of the minimally effective doses to engender all behaviors indicated a rank order of relative potency of triazolam greater than ANX3 greater than ANX4. While ANX3 was approximately 3-fold less potent than triazolam at all behavioral measures, ANX4 was less potent at engendering ataxia and procumbent posture (30-fold) than muscle relaxation, which may reflect this compound's reduced potency at alpha-1 GABA-A receptors.