Development of Novel Agents for CNS-related Diseases

描述（由申请人提供）：根据美国国家精神卫生研究所（NIMH），估计有26.2%的18岁及以上的美国人在给定的一年中患有可诊断的精神障碍。根据2004年的人口普查数字，这一比例相当于每年约6 000万人。该提案的长期目标是开发新的药物，这些药物与目前使用的抗精神病药物和抗抑郁药物相比具有更好的治疗效果。以氯氮平和奥氮平为代表的非典型抗精神病药（AAAs）或第二代抗精神病药（SGAs）由于其优越的上级副作用特征，已取代典型抗精神病药（TAAs）作为治疗精神分裂症的首选药物。然而，现在已经发现AAA产生一组新的不良事件，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种与CNS或外周中的特定受体有关。因此，本研究提案的目标有三个方面：通过验证其体内活性，将我们实验室中鉴定的新先导化合物推向临床，优化另一种新的先导化合物（SYA 038），其有可能克服与当前AAA相关的副作用，并优化第三种新的先导化合物（SYA 031），其有可能克服与5-羟色胺再摄取抑制剂（SSRIs）治疗抑郁症并提高其治疗效果。为实现该提案的目标，提出了以下具体目标：i）验证SYA 013在精神分裂症动物模型中的体内功效并进行生物利用度和药代动力学分析，ii）对新的先导化合物SYA 038进行SAR研究，在前一个MBRS周期中发现，以优化其对D2和5 HT 1A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新型抗抑郁药物，使用新鉴定的对5-羟色胺转运体（SERT）和5 HT 1A具有特异性结合亲和力的药物SYA 031作为先导。具有抑制SERT和5 HT 1A的组合能力的药物可能代表一类用于治疗抑郁症的新型药物。实现具体目标还将提供初步数据，并改善我们的研究环境，使我们在资助期结束时更具竞争力地申请NIH NIMH的非SCORE R系列赠款。 公共卫生相关性：根据美国国家心理健康研究所（NIMH）的数据，估计有26.2%的18岁及以上的美国人在某一年患有可诊断的精神障碍。根据2004年的人口普查数字，这一比例相当于每年约6 000万人。该提案的长期目标是开发新的药物，这些药物与目前使用的抗精神病药物和抗抑郁药物相比具有更好的治疗效果。为精神分裂症和抑郁症提供新药将增加与当前药物相关的不良副作用，并减少与这种使人衰弱的疾病相关的医疗保健费用。实现具体目标还将提供初步数据，并改善我们的研究环境，使我们在资助期结束时更具竞争力地申请NIH NIMH的非SCORE R系列赠款。

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.