Development of Novel Agents for CNS-related Diseases

描述(由申请人提供)：根据国家精神卫生研究所(NIMH)的数据，在给定的一年中，估计有26.2%的18岁及以上的美国人患有可诊断的精神障碍。按照2004年的人口普查数字，这一比例相当于每年约6000万人。这项提案的长期目标是开发新的药物，这些药物比目前使用的抗精神病药物和抗抑郁药物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物(AAAs)或第二代抗精神病药物(SGAs)因其优越的副作用而取代典型抗精神病药物(TAAs)成为治疗精神分裂症的首选药物。然而，AAA现在被发现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、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，这项研究提案的目标有三个：通过验证其体内活性，将我们实验室中发现的一种新铅推向临床，优化另一种可能克服当前AAA相关副作用的新铅(SYA038)，并优化第三种新铅化合物(SYA031)，其有可能克服与5-羟色胺再摄取抑制剂(SSRIs)治疗抑郁症相关的初始延迟，并提高其治疗效果。建议的具体目标如下：i)验证SYA 013在精神分裂症动物模型上的体内疗效并进行生物利用度和药代动力学分析；ii)对在上一个MBRS周期中发现的新的先导化合物SYA038进行SAR研究，以优化其与D2和5HT1A受体的亲和力，但不包括与不良事件相关的受体的高亲和力；iii)扩大我们对抗精神病药物的独家研究范围，利用新发现的与5羟色胺转运体(SERT)具有特异结合亲和力的SYA031作为先导药物。联合抑制SERT和5HT1a的药物可能代表着一类治疗抑郁症的新药物。实现具体目标还将提供初步数据并改善我们的研究环境，以便我们在资助期结束前更有竞争力地申请NIH NIMH的非分数R系列拨款。 公共卫生相关性：根据美国国家心理健康研究所(NIMH)的数据，在给定的一年中，估计有26.2%的18岁及以上的美国人患有可诊断的精神障碍。按照2004年的人口普查数字，这一比例相当于每年约6000万人。这项提案的长期目标是开发新的药物，这些药物比目前使用的抗精神病药物和抗抑郁药物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现有药物相关的不良副作用，并降低与这种令人衰弱的疾病相关的医疗成本。实现具体目标还将提供初步数据并改善我们的研究环境，以便我们在资助期结束前更有竞争力地申请NIH NIMH的非分数R系列拨款。

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.