GABA B compounds for depression and smoking cessation

描述（由申请人提供）：本申请是对RFA MH-03-008的回应，旨在组建一个治疗情绪障碍或尼古丁成瘾的国家合作药物发现小组（NCDDG-MD/NA），以开展针对这两种疾病的创新药物发现工作，并开发和验证一种推测的抗抑郁活性的新动物模型。该项目将涉及一个学术合作伙伴，加州拉霍亚的斯克里普斯研究所，以及一个工业合作伙伴，瑞士巴塞尔的诺华制药公司。提出的药理学方法是开发γ -氨基丁酸B （GABAB）受体阳性调节剂作为抗抑郁药和/或戒烟辅助药物。特异性目标1将涉及合成和改进GABAB受体阳性调节剂，对GABAB受体具有良好的选择性。特异性目标2将涉及在人、大鼠和小鼠GABAB受体测定中生物化学表征这些（GABAB）阳性调节剂的实验。还将评估药代动力学、脑渗透和对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的尼古丁自我给药中使用固定比例和渐进比例强化计划的影响。特异性目标4将评估化合物在体内和动物抑郁症模型中的作用。初步研究将评估这些化合物的潜在副作用。后续工作将评估化合物在6种抗抑郁活性模型中的作用：小鼠和大鼠强迫游泳试验、小鼠悬尾试验、大鼠嗅球切除试验和大鼠尼古丁和安非他明戒断试验。后一种测试还将提供有关化合物对药物戒断的潜在治疗作用的信息，这些戒断假设有助于复发。最后，Specific Aim 5将尝试建立并验证以嗅球切除为诱导条件，以脑奖励阈值为因变量的抑郁症动物模型（第7模型），并对推定的抗抑郁药物进行测试。这个综合的多学科研究项目专注于抑郁症和戒烟，并利用斯克里普斯和诺华科学家的专业知识，将成为开发这些疾病新疗法的创新方法。|

DESCRIPTION (provided by applicant): 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 or 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 ill 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. |