Novel Ligands that Selectively Desensitize alpha4beta nAChRs for Smoking Cessatio

描述（申请人提供）：本申请中包括的三个项目的主要假设是，尼古丁在CNS中的许多重要体内作用主要由神经元烟碱乙酰胆碱受体（nAChR），特别是α 4 β 2 nAChR的脱敏介导，其是CNS中的主要nAChR，并且是在大鼠和小鼠中受尼古丁慢性给药以及在人类中受吸烟影响最明显（上调）的一种。我们的假设有着20多年的细胞研究和尼古丁在动物体内作用的研究基础。我们最近报道了一个新的nAChR配体sazetidine-A（Saz-A）是一个选择性的a4| 32 nAChR脱敏剂。因此，其主要的体外作用是使α 4 β 2 nAChR脱敏而不影响α 3 β 4或α 7 nAChR。特别重要的是，Saz-A在体内可以在药物辨别研究中替代尼古丁，更重要的是，它减少了大鼠的尼古丁自我给药。因此，我们建议进一步深入研究Saz-A的作用，包括其在慢性给药期间的作用，以及合成和开发额外的新的选择性α 4 β 2脱敏配体。我们提出的研究包括三个项目。在项目1中，我们将使用药理学方法在体外表征nAChRs的新配体，就像我们对Saz-A所做的那样。这些体外细胞研究将确定项目2中概述的详细体内研究的最佳候选者。在项目2中，将进一步评价项目1中确定的Saz-A和其他配体对大鼠模型中尼古丁自我给药的影响。在项目3中，将进行基于Saz-A的新配体的合成，以优化新配体的药理学和药代动力学特征，这将允许选择项目2体内研究的剂量范围。此外，项目3将提供有希望的配体的急性毒性数据，并将合成项目2详细体内研究所需数量的配体。我们提出的研究的一个主要目标是，它将导致开发一类新的CNS治疗剂，选择性a4 p2 nAChR脱敏剂，以帮助戒烟。

DESCRIPTION (provided by applicant): The main hypothesis of the three projects included in this application is that many of the important in vivo effects of nicotine in the CNS are mediated mainly by the desensitization of neuronal nicotinic acetylcholine receptors (nAChRs), specifically a4p2 nAChRs, which are the major nAChR in the CNS and the one most clearly affected (up-regulated) by chronic administration of nicotine in rats and mice and by smoking in humans. Our hypothesis has deep roots in both cellular studies and studies ofthe in vivo effects of nicotine in animals going back more than 20 years. We recently reported that a new nAChR ligand sazetidine-A (Saz-A) is a selective a4|32 nAChR desensitizer. Thus its major in vitro effect is to desensitize 04(32 nAChRs without affecting either a3p4 or a7 nAChRs. Of particular importance, Saz-A in vivo can substitute for nicotine in drug discrimination studies and, even more important, it decreases nicotine self-administration in rats. We therefore propose further in depth studies of the effects of Saz-A, including its effects during chronic administration, as well as the synthesis and development of additional new selective a4p2 desensitizing ligands. Our proposed research consists of three projects. In Project 1, we will use pharmacological methods to characterize new ligands at nAChRs in vitro, as we have done for Saz-A. These in vitro cellular studies will identify the best candidates for detailed in vivo studies outlined in Project 2. In Project 2, the effects of Saz-A and additional ligands identified in project 1 will be further evaluated for their effects on nicotine self-administration in the rat model. In Project 3, synthesis of new ligands based on Saz-A will be carried out to optimize the new ligands, with respect to their pharmacology and pharmacokinetic characteristics, which will allow selection of the dose range for the in vivo studies of project 2. In addition, project 3 will provide acute toxicity data for promising ligands and will synthesize the ligands in the quantities necessary for the detailed in vivo studies in project 2. A major goal of our proposed research is that it will lead to the development a new class of CNS therapeutics, selective a4p2 nAChR desensitizers, to aid smoking cessation.