Selective alpha4beta2 nAChR Desensitizers: in vitro Pharmacological Properties

神经元烟碱型乙酰胆碱受体(NAChRs)是一种配体门控离子通道，参与多种生理功能、病理过程和药理作用。这些受体是尼古丁的初始靶标，在尼古丁成瘾的发展过程中起着至关重要的作用。此外，这些受体还可能参与其他成瘾的发展和某些中枢神经系统疾病，包括精神分裂症。 开发针对nAChRs的药物的努力主要集中在配体激活nAChRs的能力上。我们假设，尼古丁在中枢神经系统的许多体内效应主要是通过神经元nAChRs的脱敏而介导的，主要是04(32 nAChRs。基于我们对选择性脱敏a4p2 nAChRs的新型配体sazetidine-A的体外药理学特性的研究，我们进一步假设：(1)体外选择性脱敏A4(32nAChRs)的尼古丁配体将产生尼古丁的一些重要体内效应；以及(2)这种选择性a4p2 nAChRs的脱敏剂是潜在的帮助戒烟的治疗剂。基于这些假设，我们建议开发新的尼古丁疗法，基于nAChR的脱敏，而不是激活它们。 在项目1中，我们的目标是使用体外药理学方法来描述新的配体。为了实现这一目标，我们提出了四个具体目标：目标1，研究所有新配体的平衡结合特性；目标2，利用~(86)Rb外排分析研究新配体的功能特性；目标3，利用全细胞膜片钳技术研究新配体的功能特性；以及目标4，表征新配体诱导脱敏的药理学机制。 项目1的目标与项目2(动物行为模型研究)和项目3(急性毒性的药物化学和动物试验)中的拟议研究密切相关。我们希望这三个项目的合作将导致研究新药应用的候选药物，这些药物可能用于治疗尼古丁成瘾。

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are implicated in a wide range of physiological functions, pathological processes and pharmacological effects. These receptors are the initial targets of nicotine and play an essential role in the development of nicotine addiction. In addition, these receptors may also be involved in developments of other addictions and in certain CNS disorders, including schizophrenia. Efforts to develop drugs targeting nAChRs have focused mainly on the ability of ligands to activate nAChRs. We hypothesize that many of the in vivo effects of nicotine in the CNS are mediated mainly by the desensitization of neuronal nAChRs, predominantly the 04(32 nAChRs. Based on our studies of in vitro pharmacological properties of sazetidine-A, a novel ligand that selectively desensitizes a4p2 nAChRs, we further hypothesized that (1) a nicotinic ligand that selectively desensitizes a4(32 nAChRs in vitro will produce some of the important in vivo effects of nicotine; and (2) such selective desensitizers of a4p2 nAChRs are potential therapeutic agents to aid smoking cessation. Based on these hypotheses, we propose to develop novel nicotinic therapeutics based desensitization of nAChR, rather than on activation of them. In the Project 1, our objective is to use in vitro pharmacological methods to profile novel ligands. We propose four Specific Aims to accomplish the objective: Aim 1, study equilibrium binding properties of all new ligands; Aim 2, study functional properties of new ligands using 86Rb+ efflux assays; Aim 3, study functional properties of new ligands using whole-cell patch clamp techniques; and Aim 4, characterize the pharmacological mechanisms related to desensitization induced by the novel ligands. The Aims of the Project 1 are closely related to proposed research in Project 2 (studies in animal behavioral models) and Project 3 (medicinal chemistry and animal tests for acute toxicity). We hope the collaborated efforts of the three projects will lead to drug candidates for Investigative New Drug applications, which may be used for treating nicotine addiction.