Melatonin Analog PD6735 and Anxiety

描述（由申请人提供）： P2 D公司正在开发一种合成褪黑激素类似物PD 6735，用于治疗焦虑症。初步研究表明，PD 6735可以减少啮齿动物的焦虑。其他临床前研究表明，PD 6735是安全的，是MT 1和MT 2受体的高亲和力褪黑素激动剂。这项1期SBIR提案的目标是确定PD 6735在临床前啮齿动物焦虑模型中的疗效。初步研究表明，PD 6735显着影响与焦虑相关的旷场行为：冻结（不动）和饲养。不动和养育被认为是焦虑相关的措施，对临床有效的抗焦虑药物（抗焦虑药）有反应。我们建议扩展我们的初步研究，并采用旷场试验以及其他两种抗焦虑筛选试验（1）高架十字迷宫和2）防御性探针埋藏进行更详细的PD 6735剂量反应和时间过程研究。在行为测试后立即测定PD 6735血浆和脑水平以确定PD 6735水平与PD 6735的抗焦虑作用之间的关系。由于PD 6735已处于临床开发阶段，如果临床前疗效研究结果为阳性，则可以相对快速地将其作为人体抗焦虑药进行评估。我们的1期研究的具体目的是：具体目的1：确定急性PD 6735在啮齿动物旷场试验中的抗焦虑作用的时程，该试验采用褪黑激素和地西泮作为对照。具体目标二：在行为测试后立即测量特定目标1动物的血浆和脑PD 6735水平，并确定焦虑测量与血浆/脑PD 6735水平之间的关系。具体目标3：采用褪黑激素和地西泮作为对照，测定急性PD 6735在焦虑的啮齿动物高架迷宫模型中的抗焦虑作用的时间过程。此外，在行为测试后立即测量血浆和脑PD 6735水平，并确定焦虑测量与血浆/脑PD 6735水平之间的关系。具体目标4：采用褪黑激素和地西泮作为对照，确定急性PD 6735在焦虑的啮齿动物防御性戳埋模型中的抗焦虑作用的时间过程。此外，在行为测试后立即测量血浆和脑PD 6735水平，并确定焦虑测量与血浆/脑PD 6735水平之间的关系。

DESCRIPTION (Provided by applicant): P2D, Inc. is developing a synthetic melatonin analog, PD6735, for the treatment of anxiety. Preliminary Studies suggest that PD6735 reduces anxiety in rodents. Additional pre-clinical studies indicate that PD6735 is safe and is a high-affinity melatonin agonist at MT1 and MT2 receptors. The goal of this Phase 1 SBIR proposal is to determine PD6735 efficacy in pre-clinical rodent models of anxiety. Preliminary Studies indicate that PD6735 significantly affects open field behaviors associated with anxiety: freezing (immobility) and rearing. Immobility and rearing are thought to be anxiety-related measures which are responsive to clinically effective anti-anxiety drugs (anxiolytics). We propose to extend our Preliminary Studies and perform more detailed PD6735 dose-response and time-course studies employing the open field test as well as two other anxiolytic screening tests: 1) the elevated plus maze, and 2) defensive prod-burying. Immediately after behavioral testing PD6735 plasma and brain levels will be assayed to determine the relationship between PD6735 levels and PD6735's anxiolytic effects. As PD6735 is already in clinical development, it can be evaluated relatively rapidly as an anxiolytic in humans should pre-clinical efficacy studies be positive. The Specific Aims of our Phase 1 study are: Specific Aim 1: Determine the time course of the anti-anxiety effect of acute PD6735 in the rodent open field test employing melatonin and diazepam as controls. Specific Aim 2: Measure plasma and brain PD6735 levels in Specific Aim 1 animals immediately after behavioral testing and determine the relationship between anxiety measures and plasma/brain PD6735 levels. Specific Aim 3: Determine the time course of the anti-anxiety effect of acute PD6735 in the rodent elevated plus maze model of anxiety employing melatonin and diazepam as controls. Further, measure plasma and brain PD6735 levels immediately after behavioral testing and determine the relationship between anxiety measures and plasma/brain PD6735 levels. Specific Aim 4: Determine the time course of the anti-anxiety effect of acute PD6735 in the rodent defensive prod-burying model of anxiety employing melatonin and diazepam as controls. Further, measure plasma and brain PD6735 levels immediately after behavioral testing and determine the relationship between anxiety measures and plasma/brain PD6735 levels.