Chemistry and Pharmacology of a New Nicotine Ligands

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、图雷特综合征、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。

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.