Development of Novel Agents for CNS-related Diseases

描述（由申请人提供）：根据美国国家心理健康研究所（NIMH）的数据，在某一年中，18岁及以上的美国人中估计有26.2%的人患有可诊断的精神障碍。根据2004年的人口普查数据，这一比例转化为每年约6000万人。这项建议的长期目标是开发新的药物，以改善目前使用的抗精神病药和抗抑郁药的治疗效果。以氯氮平和奥氮平为代表的非典型抗精神病药物（AAAs）或第二代抗精神病药物（SGAs），由于其优越的副作用，已经取代了典型的抗精神病药物（TAAs），成为治疗精神分裂症的首选药物。然而，现在已经发现AAAs会产生一系列新的不良事件，包括体重增加、肥胖、II型糖尿病、癫痫发作、低血压、高脂血症和心血管疾病（CVD）。这些新的副作用中有几个与中枢神经系统或外周的特定受体有关。因此，本研究计划的目标有三个方面：通过验证其体内活性，将实验室确定的新先导物推向临床；优化另一种新先导物（SYA038），有可能克服与当前AAAs相关的副作用；优化第三种新先导化合物（SYA031），有可能克服与血清素再摄取抑制剂（SSRIs）治疗抑郁症相关的初始延迟，并提高其治疗效果。为达致建议的目标，建议订定以下具体目标：i)验证SYA 013在精神分裂症动物模型中的体内疗效，并进行生物利用度和药代动力学分析；ii)对在先前MBRS周期中发现的新的先导化合物SYA038进行SAR研究，以优化其对D2和5HT1A受体的亲和力，但排除与不良事件相关的受体的高亲和力；iii)将我们对抗精神病药物的独家关注扩展到关注新型抗抑郁药物，使用新发现的具有血清素转运体（SERT）和5HT1A特异性结合亲和力的药物SYA031作为先导。联合抑制SERT和5HT1A的药物可能代表了治疗抑郁症的一类新药物。实现具体目标还将提供初步数据，改善我们的研究环境，使我们在资助期结束时更有竞争力申请NIH NIMH的非score r系列资助。

DESCRIPTION (provided by applicant): According to the National Institute of Mental Health (NIMH), an estimated 26.2% of Americans ages 18 and above suffer from a diagnosable mental disorder in a given year. This percentage translates to about 60 million people per year using 2004 census figures. The long term goal of this proposal is to develop new agents that have improved therapeutic profiles over the current antipsychotics and antidepressants in use. Atypical Antipsychotic Agents (AAAs) or Second Generation Antipsychotics (SGAs), typified by clozapine and olanzapine, have replaced typical antipsychotic agents (TAAs) as the drugs of choice for the treatment of schizophrenia due to their superior side effect profiles. However, AAAs have now been found to produce a new set of adverse events including weight gain, obesity, type II diabetes, seizures, hypotension, hyperlipidemia and cardiovascular disease (CVD). Several of these new side effects have been linked to specific receptors in the CNS or the periphery. Thus, the goal of this research proposal is three-fold: to move a new lead identified in our laboratories towards the clinic by validating its in vivo activities, to optimize another new lead (SYA038) with the potential to overcome the side effects associated with the current AAAs and to optimize a third new lead compound (SYA031) with the potential to overcome the initial delay associated with serotonin reuptake inhibitors (SSRIs) in the treatment of depression and to improve their therapeutic efficacy. The following specific aims are proposed to achieve the objectives of the proposal: i) To validate the in vivo efficacy of SYA 013 in animal models of schizophrenia and to conduct bioavailability and pharmacokinetic analyses, ii) To conduct SAR studies on a new lead compound, SYA038, discovered during the previous MBRS cycle in order to optimize its affinity to both D2 and 5HT1A receptors but exclude high affinity at receptors linked to the adverse events, iii) To expand our exclusive focus on antipsychotic agents to a focus on novel antidepressants using a newly identified agent SYA031 with specific binding affinity for the serotonin transporter (SERT) and 5HT1A as a lead. Drugs with a combined capacity to inhibit SERT and 5HT1A may represent a novel class of drugs for treating depression. Achieving the specific aims will also provide preliminary data and improve our research environment such that we would become more competitive to apply for non-SCORE R-series grants from the NIH NIMH by the end of the grant period. PUBLIC HEALTH RELEVANCE: According to the National Institute of Mental Health (NIMH), an estimated 26.2% of Americans ages 18 and above suffer from a diagnosable mental disorder in a given year. This percentage translates to about 60 million people per year using 2004 census figures. The long term goal of this proposal is to develop new agents that have improved therapeutic profiles over the current antipsychotics and antidepressants in use. Providing new drugs for Schizophrenia and depression will elevate adverse side-effects associated with the current drugs and reduce health care cost associated with this debilitating illness. Achieving the specific aims will also provide preliminary data and improve our research environment such that we would become more competitive to apply for non-SCORE R-series grants from the NIH NIMH by the end of the grant period.