National cooperative drug discovery groups for treatment of mood disorder

本申请是响应RFA MH-03-008形成国家合作药物发现] 情绪障碍或尼古丁成瘾治疗小组(NCDDG-MD/NA)工作] 针对这两种疾病的创新药物发现，以及假定的抗抑郁活性新动物模型的开发和验证。这个项目将涉及一个学术合作伙伴，斯克里普斯] 位于加利福尼亚州拉霍亚的诺华制药公司及其工业合作伙伴巴塞尔诺华制药公司， 瑞士。建议的药理学方法是开发伽马-氨基丁酸B(GABAB)受体阳性调节剂，作为抗抑郁药和/或帮助戒烟。具体目标1将涉及对GABAB受体具有良好选择性的GABAB受体正性调节剂的合成和精制。具体目标2将涉及在人、大鼠和小鼠的GABAB受体分析中以生物化学的方式表征这些GABAB阳性调节剂的实验。 还将评估药物动力学、脑渗透性以及与其他受体和通道的结合亲和力。具体目标3将评估这些化合物在尼古丁依赖大鼠中使用固定比率和递增比率强化计划的尼古丁自我给药的效果。 具体目标4将评估这些化合物在体内和抑郁症动物模型中的效果。初步研究将评估这些化合物的潜在副作用。随后的工作将评估化合物在6个抗抑郁活性模型中的效果：小鼠和大鼠的强迫游泳试验，小鼠的尾部悬吊试验，大鼠的嗅球切除试验，以及大鼠的尼古丁和苯丙胺戒断。后一项测试还将提供关于药物戒断的潜在治疗效果的信息，假设这些化合物有助于复发。最后，特殊目的5将尝试建立和验证一种新的抑郁动物模型(模型7)，以嗅球切除为诱导条件，以脑奖赏阈值为因变量，并测试可能的抗抑郁药物。这一综合的多学科研究计划侧重于 抑郁和戒烟，并利用斯克里普斯和诺华科学家的专业知识，将是开发治疗这些疾病的新疗法的创新方法。

This application is in response to RFA MH-03-008 to form a National Cooperative Drug Discovery] Group for the Treatment of Mood Disorders or Nicotine Addiction (NCDDG-MD/NA) to work on] innovative drug discovery for these two disorders, and the development and validation of a putative new animal model of antidepressant activity. This project will involve an academic partner, The Scripps] Research Institute, La Jolla, California, and an industrial partner, Novartis Pharma AG, Basel, Switzerland. The pharmacological approach proposed is the development of gamma-aminobutyric acid B (GABAB) receptor positive modulators as antidepressants and/or aids to smoking cessation. Specific Aim 1 will involve the synthesis and refinement of GABAB receptor positive modulators with good selectivity for the GABAB receptor. Specific Aim 2 will involve experiments characterizing these GABAB positive modulators biochemically in human, rat and mouse GABAB receptor assays. Pharmacokinetics, brain penetration, and binding affinities for other receptors and channels will also be evaluated. Specific Aim 3 will assess the effects of these compounds in nicotine self-administration using both fixed-ratio and progressive ratio schedules of reinforcement in nicotine-dependent rats. Specific Aim 4 will assess the effects of the compounds in vivo and in animal models of depression. Initial studies will evaluate the potential side-effect profile of these compounds. Subsequent work will evaluate the effects of the compounds in 6 models of antidepressant activity: the forced swim test in mice and rats, the tail suspension test in mice, the olfactory bulbectomy test in rats, and nicotine and amphetamine withdrawal in rats. The latter test will also provide information about potential therapeutic effects of the compounds on drug withdrawal hypothesized to contribute to relapse. Finally, Specific Aim 5 will attempt to develop and validate a new animal model of depression (7th model) involving olfactory bulbectomy as the inducing condition and brain reward thresholds as the dependent variable, and test putative antidepressant drugs. This integrated multidisciplinary research program focusing on both depression and smoking cessation and capitalizing on the expertise of both Scripps and Novartis scientists will be an innovative approach to the development of new therapeutics for these disorders.