Muscarinic agonists for neurological disorders

描述(由申请人提供)：拟议研究的目的是开发设计治疗神经疾病的化合物的新方法。胆碱能活动的变化与包括阿尔茨海默病和精神分裂症在内的各种病理条件有关。M受体激动剂可能有助于恢复与神经疾病相关的胆碱能活动的化学失衡。不幸的是，M受体激动剂由于激活多种受体亚型而产生不良副作用的倾向阻碍了新疗法的发展。提出了一种药物开发的综合方法，将来自分子生物学和计算化学研究的信息用于设计和开发选择性M受体激动剂。嵌合受体将被产生，以帮助确定分子与M受体亚型结合的位置。为了了解激动剂如何稳定受体的活性形式，我们将建立M受体的分子模型。现有的配体将被对接到M受体模型中，以验证在嵌合受体研究中发现的相互作用，并识别代表选择性配体上功能基团结合位置的氨基酸残基。将设计和合成新的化合物，以利用从分子生物学和计算化学研究中获得的信息。化合物将在表达M受体亚型的细胞系中表征受体结合特性和功能活性。在阿尔茨海默病和精神分裂症的动物模型中，显示出高活性和选择性的毒扁豆碱激动剂将分别在增强记忆功能和抗精神病活性的功能分析中得到进一步检验。这里概述的研究将为治疗神经疾病提供新的方法，包括阿尔茨海默病和精神分裂症。

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.