Chemistry and Pharmacology of a New Nicotine Ligands

描述(由申请人提供)：神经元尼古丁受体(NAChRs)作为治疗中枢神经系统和周围神经系统疾病的靶点具有非常大的前景。针对nAChRs的药物有可能治疗神经退行性疾病、运动障碍、抽动症、精神分裂症、注意力缺陷障碍、焦虑和疼痛，以及尼古丁成瘾。我们的总体目标是解决针对nAChR亚型选择性药物的不足。为此，我们将开展研究，以合成和/或化学修饰属于已知对nAChRs具有高亲和力的几个产品家族之一的分子。每一种制备的化学实体都将在一系列检测中进行评估，以测量其与哺乳动物细胞中稳定表达的七种不同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。本研究的目的是为研究这些受体和关键的结构活性信息提供新的药理学工具，这些信息可以引导或有助于开发治疗人类疾病的nAChR亚型选择性药物。为了达到这些目标，我们将实现以下具体目标： 根据已知的在nAChR上具有重要性质的分子进行合成和化学修饰，这些分子是：表巴替丁(在所有测试的nAChR亚型中都是高亲和力激动剂，但Alpha7除外)，胞嘧啶(在含有β4亚基的受体上是激动剂，在含有β2亚基的受体上是部分激动剂)，A-85380(在β亚基受体上是高亲和力激动剂)，以及Irsodine(与含有β亚基的受体具有高亲和力的竞争性拮抗剂)。 通过分析在哺乳动物细胞中稳定表达的七种nAChR亚型的结合亲和力，鉴定化学工作中制备的每个配体作用于尼古丁受体的能力，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。功能活性将使用已建立的86RbC1外排分析和/或全细胞膜片钳测量进行评估。

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.