Muscarinic agonists for neurological disorders

描述（由申请人提供）：拟议研究的目的是开发用于设计治疗神经系统疾病的化合物的新方法。胆碱能活性的变化与包括阿尔茨海默病和精神分裂症在内的多种病理状况有关。毒蕈碱激动剂可能有助于恢复与神经系统疾病相关的胆碱能活性的化学失衡。不幸的是，由于多种受体亚型的活化，毒蕈碱激动剂产生不希望的副作用的倾向阻碍了新疗法的开发。提出了一种药物开发的综合方法，即分子生物学和计算化学研究的信息用于选择性毒蕈碱激动剂的设计和开发。将产生嵌合受体以帮助确定分子与毒蕈碱受体亚型结合的位置。将创建毒蕈碱受体的分子模型，以了解激动剂如何稳定受体的活性形式。现有的配体将对接到毒蕈碱受体模型中，以验证嵌合受体研究中发现的相互作用，并确定代表选择性配体上官能团结合位点的氨基酸残基。新的化合物将被设计和合成，以利用来自分子生物学和计算化学研究的信息。将表征化合物在表达毒蕈碱受体亚型的细胞系中的受体结合性质和功能活性。显示高活性和选择性的毒蕈碱激动剂将分别在阿尔茨海默病和精神分裂症的动物模型中在增强记忆功能和抗精神病活性的功能测定中进一步检查。这里概述的研究将为治疗神经系统疾病（包括阿尔茨海默病和精神分裂症）提供新的方法。

DESCRIPTION (provided by applicant): The purpose of the proposed research is to develop new approaches for designing compounds to treat neurological disorders. Changes in cholinergic activity have been implicated in a variety of pathological conditions including Alzheimer's disease and schizophrenia. Muscarinic agonists might be helpful in restoring the chemical imbalances in cholinergic activity associated with neurological disorders. Unfortunately, the development of new therapies is hindered by the propensity for muscarinic agonists to produce unwanted side effects due to activation of multiple receptor subtypes. An integrated approach to drug development is proposed whereby information from molecular biological and computational chemical studies is used in the design and development of selective muscarinic agonists. Chimeric receptors will be generated to help determine where molecules bind to muscarinic receptor subtypes. Molecular models of muscarinic receptors will be created in order to understand how agonists stabilize the active form of the receptor. Existing ligands will be docked into the muscarinic receptor model to verify interactions discovered in studies of chimeric receptors and to identify amino acid residues that represent binding sites for functional groups on selective ligands. New compounds will be designed and synthesized to take advantage of the information derived from the molecular biological and computational chemical studies. Compounds will be characterized for receptor binding properties and functional activities in cell lines expressing muscarinic receptor subtypes. Muscarinic agonists that display high activity and selectivity will be examined further in functional assays for enhancement of memory function and antipsychotic activity in animal models of Alzheimer's disease and schizophrenia, respectively. The studies outlined here will provide new approaches for the treatment of neurological disorders, including Alzheimer's disease and schizophrenia.