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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。最近的研究集中在了解GABA-A受体机制在苯二氮卓类药物（BZs）的行为影响。两种新开发的化合物ANX3和ANX4是镇静催眠药BZ三唑仑的8-乙酰基类似物。在人GABA-A受体中，ANX3和ANX4的总体疗效和效价谱与三唑安定相似；然而，在低浓度下，与ANX3和三唑仑相比，ANX4对含有GABA-A受体的α -1亚基的效力降低。我们评估了ANX4的功能选择性在多大程度上导致了与三唑仑和ANX3不同的抗焦虑和镇静运动作用。在恒河猴中评估了抗焦虑样活性。在松鼠猴中评估了可观察到的行为效果，包括测量肌肉松弛、共济失调和平卧姿势。ANX3、ANX4和三唑仑诱导抗焦虑样作用，在所有行为测量中均有可靠的效果。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ANX3大于ANX4。虽然在所有行为测量中，ANX3的效力大约比三唑仑低3倍，但ANX4在产生运动失调和卧姿方面的效力比肌肉放松低30倍，这可能反映了该化合物对α -1 GABA-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.