Selective alpha4beta2 nAChR Desensitizers: in vitro Pharmacological Properties

选择性 α4β2 nAChR 脱敏剂：体外药理学特性

• 批准号: 8435488
• 负责人: YINGXIAN XIAO
• 金额: $ 29.77万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8435488
• 关键词: Acetylcholine; Acute; Affect; Affinity; Agonist; Americas; Animal Model; Animal Testing; Animals; Bathing; Behavioral; Behavioral Model; Binding; Biological Assay; Brain; Cell model; Cells; Central Nervous System Diseases; Chronic; Cigarette; Cues; Development; Dose; Drosophila acetylcholine receptor alpha-subunit; Drug Targeting; Equilibrium; Evaluation; Exposure to; Gated Ion Channel; Goals; Health Care Costs; Human; In Vitro; Individual; Kinetics; Knock-in Mouse; Knock-out; Lead; Ligands; Measurement; Measures; Mediating; Methods; Modeling; Mus; Neurons; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Agonists; Nicotinic Receptors; Patch-Clamp Techniques; Pathologic Processes; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physiological; Play; Property; Public Health; Radiolabeled; Rattus; Recovery; Recovery of Function; Relative (related person); Reporting; Research; Role; Schizophrenia; Self Administration; Signal Transduction; Simulate; Smoke; Smoking; Testing; Therapeutic; Therapeutic Agents; Time; Tobacco use; Toxic effect; Tube; addiction; base; cigarette smoking; desensitization; design; drug candidate; drug development; drug discovery; epibatidine; experience; improved; in vivo; insight; mouse model; neurophysiology; novel; patch clamp; radiotracer; receptor; receptor binding; receptor density; receptor function; research and development; smoking cessation; varenicline

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.

神经元烟碱乙酰胆碱受体（nAChR）是一种配体门控的离子通道，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最初靶点，在尼古丁成瘾的发展中起着至关重要的作用。 此外，这些受体也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。 开发靶向nAChR的药物的努力主要集中在配体激活nAChR的能力上。我们假设尼古丁在中枢神经系统中的许多体内作用主要是由神经元nAChR（主要是04（32）nAChR）的脱敏介导的。基于我们对沙泽替丁-A（一种选择性脱敏α 4 β 2 nAChR的新型配体）的体外药理学性质的研究，我们进一步假设（1）在体外选择性脱敏α 4 β 2 nAChR的烟碱配体将产生尼古丁的一些重要体内作用;和（2）α 4 β 2 nAChR的这种选择性脱敏剂是帮助戒烟的潜在治疗剂。基于这些假设，我们建议开发基于nAChR脱敏的新型烟碱治疗剂，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。我们提出了四个具体目标来实现这一目标：目标1，研究所有新配体的平衡结合特性;目标2，使用86 Rb+流出试验研究新配体的功能特性;目标3，使用全细胞膜片钳技术研究新配体的功能特性;目标4，表征与新配体诱导的脱敏相关的药理学机制。 项目1的目的与项目2（动物行为模型研究）和项目3（药物化学和急性毒性动物试验）中的拟议研究密切相关。我们希望这三个项目的合作努力将导致研究性新药申请的候选药物，这些药物可能用于治疗尼古丁成瘾。