Muscarinic agonists for neurological disorders
用于治疗神经系统疾病的毒蕈碱激动剂
基本信息
- 批准号:7252510
- 负责人:
- 金额:$ 21.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-08-08 至 2009-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffinityAgonistAlzheimer&aposs DiseaseAmino AcidsAnimal ModelAntipsychotic AgentsBindingBinding SitesBiochemicalBiologicalBiological AssayBrainCarbacholCell LineChemicalsCholinergic AgentsCollectionConditionDataDevelopmentDockingElectrostaticsEnvironmentEstersFeedbackHydrogen BondingIndividualInstitutesLeadLengthLibrariesLigand BindingLigandsLinkMembraneMemoryModelingModificationMolecularMotorMuscarinic Acetylcholine ReceptorMuscarinic AgonistsMuscarinic M3 ReceptorPhasePropertyPurposeQuinuclidinesResearchRoleRunningSchizophreniaScreening procedureSensorySite-Directed MutagenesisTechniquesThiadiazolesTransmembrane Domainaqueousbasecholinergicdesigndrug developmentextracellularfunctional groupmolecular dynamicsmolecular modelingnervous system disordernovelnovel strategiesprepulse inhibitionreceptorreceptor bindingxanomeline
项目摘要
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.
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,并鉴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提供新的方法,包括阿尔茨海默病和精神分裂症。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
On again, off again effects of gonadectomy on the acoustic startle reflex in adult male rats.
性腺切除术对成年雄性大鼠听觉惊跳反射的影响。
- DOI:10.1016/j.physbeh.2006.10.010
- 发表时间:2007
- 期刊:
- 影响因子:2.9
- 作者:Turvin,JackC;MesserJr,WilliamS;Kritzer,MaryF
- 通讯作者:Kritzer,MaryF
Theoretical and experimental studies of the isomeric protonation in solution for a prototype aliphatic ring containing two nitrogens.
含两个氮原子的原型脂肪环溶液中异构质子化的理论和实验研究。
- DOI:10.1021/jp9082085
- 发表时间:2010
- 期刊:
- 影响因子:0
- 作者:Nagy,PeterI;Maheshwari,Aditya;Kim,Yong-Wah;MesserJr,WilliamS
- 通讯作者:MesserJr,WilliamS
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WILLIAM S MESSER其他文献
WILLIAM S MESSER的其他文献
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{{ truncateString('WILLIAM S MESSER', 18)}}的其他基金
MOLECULAR STUDIES OF MUSCARINIC RECEPTOR SUBTYPES
毒蕈碱受体亚型的分子研究
- 批准号:
2655535 - 财政年份:1997
- 资助金额:
$ 21.8万 - 项目类别:
DEVELOPMENT OF AMIDINES AS SELECTIVE MUSCARINIC AGONISTS
脒作为选择性毒蕈碱激动剂的开发
- 批准号:
6258840 - 财政年份:1997
- 资助金额:
$ 21.8万 - 项目类别:
MOLECULAR STUDIES OF MUSCARINIC RECEPTOR SUBTYPES
毒蕈碱受体亚型的分子研究
- 批准号:
6248413 - 财政年份:1997
- 资助金额:
$ 21.8万 - 项目类别:
MOLECULAR STUDIES OF MUSCARINIC RECEPTOR SUBTYPES
毒蕈碱受体亚型的分子研究
- 批准号:
2873196 - 财政年份:1997
- 资助金额:
$ 21.8万 - 项目类别:
MOLECULAR STUDIES OF MUSCARINIC RECEPTOR SUBTYPES
毒蕈碱受体亚型的分子研究
- 批准号:
2038268 - 财政年份:1997
- 资助金额:
$ 21.8万 - 项目类别:
DEVELOPMENT OF AMIDINES AS SELECTIVE MUSCARINIC AGONISTS
脒作为选择性毒蕈碱激动剂的开发
- 批准号:
2269099 - 财政年份:1994
- 资助金额:
$ 21.8万 - 项目类别:
Muscarinic agonists for neurological disorders
用于治疗神经系统疾病的毒蕈碱激动剂
- 批准号:
6824987 - 财政年份:1994
- 资助金额:
$ 21.8万 - 项目类别:
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