Chemistry and Pharmacology of a New Nicotine Ligands

新型尼古丁配体的化学和药理学

• 批准号: 7250073
• 负责人: ALAN Paul KOZIKOWSKI
• 金额: $ 28.88万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250073
• 关键词: Address; Adrenergic Agents; Adrenergic Agonists; Adrenergic Antagonists; Affinity; Agonist; Alkaloids; Alzheimer' s Disease; Antibodies; Anxiety; Asthma; Attention Deficit Disorder; Binding; Biological; Biological Assay; Biological Models; Bromine; Bungarotoxins; Cardiovascular Diseases; Cells; Central Nervous System Diseases; Chemicals; Chemistry; Clinical; Conotoxin; Cytosine; Data; Development; Disease; Dyskinetic syndrome; Erythrina; Extracellular Domain; Family; Family member; Gilles de la Tourette syndrome; Goals; Histamine; In Vitro; Lead; Learning; Ligands; Location; Mammalian Cell; Marines; Measurement; Measures; Mediating; Messenger RNA; Migraine; Modification; Morbidity - disease rate; Nervous system structure; Neurodegenerative Disorders; Neurons; Nicotine; Nicotine Dependence; Nicotinic Agonists; Nicotinic Receptors; Numbers; Pain; Parkinson Disease; Pathology; Peptides; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Play; Positioning Attribute; Property; Purpose; Pyridones; Relative (related person); Research; Role; Schizophrenia; Serotonin; Smoking; Snails; Snakes; Stomach; Structure; Study Subject; System; Testing; Toxin; Vasomotor; Work; Xenopus oocyte; adrenergic; analog; base; channel blockers; chemical synthesis; cytisine; epibatidine; erysodine; erythroidine; human disease; in vivo; member; mortality; patch clamp; protein distribution; receptor; response; therapeutic target; tool

DESCRIPTION (provided by applicant): Neuronal nicotinic receptors (nAChRs) hold very considerable promise as therapeutic targets for treatments of disorders of the CNS and peripheral nervous systems. Drugs aimed at nAChRs have potential for the treatment of neurodegenerative disorders, dyskinesias, Tourette's syndrome, schizophrenia, attention deficit disorder, anxiety and pain, as well as nicotine addiction. Our overall objective is to address the deficiency in drugs selective for nAChR subtypes. To do this, we will carry out studies to synthesize and/or chemically modify molecules belonging to one of several families of products known to have high affinities for nAChRs. Each of the chemical entities that is prepared will be evaluated in a battery of assays to measure its binding affinity at seven different nAChR receptor subtypes stably expressed in mammalian cells and to determine its functional activity as an agonist, competitive antagonist or noncompetitive antagonist. The goals of this research are to provide new pharmacological tools for studies of these receptors and the critical structure activity information that can lead or contribute to the development of nAChR subtype selective drugs to treat human diseases. To meet these objectives, we will pursue the following specific aims: To conduct synthesis and chemical modifications based on molecules already known to possess important properties at nAChR, namely: epibatidine (a high affinity agonist at all nAChR subtypes tested except alpha7), cytosine (an agonist at receptors containing beta4 subunits and a partial agonist at receptors containing beta2subunits), A-85380 (a high affinity agonist at receptors beta subunits), and erysodine (a competitive antagonist with high affinity for receptors containing beta subunits). To characterize each of the ligands prepared in the chemistry effort for their ability to act at nicotinic receptors by assaying its binding affinities at seven nAChR subtypes stably expressed in mammalian cells, and to determine if it has agonist, competitive antagonist or noncompetitive antagonist activity. Functional activity will be evaluated using established 86RbC1 efflux assays and/or whole cell patch clamp measurements.

描述（由申请人提供）：神经元烟碱受体（nAChR）作为治疗CNS和外周神经系统疾病的治疗靶点具有非常可观的前景。针对nAChR的药物具有治疗神经退行性疾病、运动障碍、抽动秽语综合症、精神分裂症、注意力缺陷障碍、焦虑和疼痛以及尼古丁成瘾的潜力。我们的总体目标是解决nAChR亚型选择性药物的不足。为此，我们将进行研究，以合成和/或化学修饰属于已知对nAChRs具有高亲和力的几种产品家族之一的分子。将在一系列试验中评价制备的每种化学实体，以测量其与哺乳动物细胞中稳定表达的7种不同nAChR受体亚型的结合亲和力，并确定其作为激动剂、竞争性拮抗剂或非竞争性拮抗剂的功能活性。本研究的目的是为这些受体的研究提供新的药理学工具和关键的结构活性信息，可以导致或有助于开发nAChR亚型选择性药物来治疗人类疾病。为了实现这些目标，我们将努力实现以下具体目标： 基于已知在nAChR具有重要特性的分子进行合成和化学修饰，即：蛙素（除α 7外，所有测试的nAChR亚型的高亲和力激动剂），胞嘧啶（含β 4亚单位受体激动剂和含β 2亚单位受体部分激动剂），A-85380（对受体β亚基的高亲和力激动剂）和赤藓定（对含有β亚基的受体具有高亲和力的竞争性拮抗剂）。 通过测定在哺乳动物细胞中稳定表达的7种nAChR亚型的结合亲和力，表征化学工作中制备的每种配体作用于烟碱受体的能力，并确定其是否具有激动剂、竞争性拮抗剂或非竞争性拮抗剂活性。将使用已建立的86 RbC 1外排试验和/或全细胞膜片钳测量评价功能活性。

项目成果

Synthesis and pharmacological characterization of bivalent ligands of epibatidine at neuronal nicotinic acetylcholine receptors.

神经元烟碱乙酰胆碱受体的皮巴替丁二价配体的合成和药理学表征。

• DOI: 10.1016/j.bmcl.2003.10.071
• 发表时间: 2004
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Wei,Zhi-Liang;Xiao,Yingxian;Kellar,KennethJ;Kozikowski,AlanP
• 通讯作者: Kozikowski,AlanP

Novel pyridyl ring C5 substituted analogues of epibatidine and 3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine (A-84543) as highly selective agents for neuronal nicotinic acetylcholine receptors containing beta2 subunits.

• DOI: 10.1021/jm0492406
• 发表时间: 2005-03
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Zhi-Liang Wei;Yingxian Xiao;Hongbin Yuan;Maryna Baydyuk;P. Petukhov;J. Musachio;K. Kellar;A. Kozikowski

Acetylenic pyridines for use in PET imaging of nicotinic receptors.

用于烟碱受体 PET 成像的乙炔吡啶。

• DOI: 10.1002/cmdc.200600220
• 发表时间: 2007
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Kozikowski,AlanP;Chellappan,SheelaK;Henderson,David;Fulton,Roger;Giboureau,Nicolas;Xiao,Yingxian;Wei,Zhi-Liang;Guilloteau,Denis;Emond,Patrick;Dolle,Frederic;Kellar,KennethJ;Kassiou,Michael
• 通讯作者: Kassiou,Michael

Chemical medicine: novel 10-substituted cytisine derivatives with increased selectivity for alpha4beta2 nicotinic acetylcholine receptors.

化学药物：新型10位取代金雀花碱衍生物，对α4β2烟碱乙酰胆碱受体具有更高的选择性。

• DOI: 10.1002/cmdc.200700073
• 发表时间: 2007
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Kozikowski,AlanP;Chellappan,SheelaK;Xiao,Yingxian;Bajjuri,KrishnaMohan;Yuan,Hongbin;Kellar,KennethJ;Petukhov,PavelA
• 通讯作者: Petukhov,PavelA