Nicotinic Ligands as Smoking Cessation Agents

作为戒烟剂的烟碱配体

• 批准号: 7270249
• 负责人: WERNER TUECKMANTEL
• 金额: $ 6.51万
• 依托单位: PSYCHOGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-15 至 2007-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7270249
• 关键词: Accounting; Adult; Adverse effects; Affinity; Agonist; Animal Experiments; Animal Testing; Animals; Arts; Azetidines; Behavior; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Cells; Cessation of life; Chairperson; Chantix; Chemistry; Clinical Trials; Data; Development; Discrimination; Disease; Evaluation; Exhibits; Ganglia; Goals; Health; Human; In Vitro; Investigational Drugs; Laboratory Research; Lead; Ligand Binding; Ligands; Mediator of activation protein; Medical center; Mississippi; Modeling; Myxoid cyst; Nausea; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Numbers; Organic Synthesis; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Property; Psychiatry; Public Health; Pyrrolidines; Quality Control; Rate; Rattus; Research; Series; Side; Smoke; Smoker; Stimulus; Students; Tobacco use; United States Food and Drug Administration; Universities; Ursidae Family; Walkers; Week; Work; addiction; analog; azetidine; base; design; drug discrimination; experience; high school; in vivo; laboratory facility; nicotine replacement; novel; professor; pyridine; pyrrolidine; receptor; smoking cessation; success; varenicline

DESCRIPTION (provided by applicant): Tobacco use and nicotine addiction are an immense burden on the public health. There are an estimated 44.5 million (21%) adult smokers and an estimated 3.75 million (22%) high school student smokers in the US. Tobacco use is responsible for over 440,000 deaths per year in the US, which accounts for 1 in every 5 total deaths. Approximately 70% of the adult smokers want to quit. However, only 5-10% succeeds each year. Their inability to quit, even with full understanding of the negative health consequences, is testament to the addicting power of nicotine. Numerous studies showed that neuronal nicotinic acetylcholine receptors (nAChRs) are major mediators in brain for the development of addiction to smoking. Among major nAChR subtypes in brain, nAChRs containing both a4 and ¿2 subunits are essential for nicotine addiction. The current leading treatment for nicotine addiction is nicotine replacement therapy. However, with meager success rates of 10-20%, new therapies are greatly needed. Very recently, Pfizer's Chantix(r) (varenicline) was approved by the FDA as a smoking cessation drug. Varenicline is a partial agonist at the a4¿2 nAChR subtype. Clinical trials showed that varenicline helped up to 45% of smokers stay smoke free for up to 12 weeks. This result validates the a4¿2 subtype as a target for smoking cessation. However, varenicline has almost full agonist activity at the a3¿4 and a7 subtypes, which may lead to side effects such as nausea seen in 30% of the patients. For any disease state as prevalent as nicotine addiction, it is essential to have a number of treatment options. Acenta Discovery and its collaborators have embarked on the goal to develop alternative a4¿2-selective nAChR ligands as a treatment for smoking cessation. A series of such ligands have previously been prepared that bear at C3 of their pyridine ring an azetidine or pyrrolidine connected through a CH2O linker, and a lipophilic side chain on C5. Many of these ligands are very potent and selective. One lead, sazetidine-A, exhibits subnanomolar binding affinity and >104-fold selectivity for the a4¿2 over the ganglionic a3¿4 subtype. Pharmacologically, sazetidine-A is quite novel as a 'silent desensitizer'. It desensitizes a4¿2 nAChRs without activating them and maintains them in their desensitized state. Functional assays revealed that sazetidine-A, in contrast to varenicline, does not show agonist activity at either the a4¿2 or a3¿4 nAChR subtypes. Notably, initial work in animals revealed that it also has nicotine-like discriminative stimulus effects. With this unique lead compound, we would like the opportunity to study in more detail the SAR for sazetidine-A. The goals of this proposal are: (1) design and synthesize a series of sazetidine-A analogs based on preliminary data; (2) assay the analogs for binding and function with an array of nAChR subtypes; (3) select the most promising analogs for nicotine discrimination animal experiments. Ideally, this work will lead into the development of new a4¿2 subtype selective nicotinic ligands to be used for smoking cessation therapy.

描述（由申请人提供）：烟草使用和尼古丁成瘾是公共健康的巨大负担。美国估计有4450万（21%）成年吸烟者和375万（22%）高中生吸烟者。在美国，烟草使用每年导致超过44万人死亡，占总死亡人数的五分之一。大约70%的成年吸烟者想要戒烟。每年只有5-10%的人成功。他们无法戒烟，即使充分了解负面的健康后果，证明了尼古丁的成瘾力量。大量研究表明，神经元烟碱乙酰胆碱受体（nAChRs）是大脑中吸烟成瘾形成的主要介质。在大脑中的主要nAChR亚型中，含有α 4和α 2亚基的nAChR是尼古丁成瘾所必需的。目前治疗尼古丁成瘾的主要方法是尼古丁替代疗法。然而，由于成功率仅为10- 20%，因此非常需要新的治疗方法。最近，辉瑞公司的Chantix（r）（伐尼克兰）被FDA批准为戒烟药物。伐伦克林是a4 ² 2 nAChR亚型的部分激动剂。临床试验表明，伐尼克兰帮助高达45%的吸烟者保持戒烟长达12周。这一结果验证了a4 <$2亚型作为戒烟的目标。然而，伐尼克兰在a3 <$4和a7亚型上几乎具有完全的激动剂活性，这可能导致30%的患者出现恶心等副作用。对于任何像尼古丁成瘾这样普遍的疾病状态，有一些治疗方案是必不可少的。Acenta Discovery及其合作者已经着手开发替代性α 4 <$2选择性nAChR配体作为戒烟治疗的目标。先前已经制备了一系列这样的配体，其在其吡啶环的C3处带有通过CH 2 O接头连接的氮杂环丁烷或吡咯烷，并且在C5上带有亲脂性侧链。这些配体中的许多是非常有效和选择性的。一种先导化合物sazetidine-A对a4 <$2的结合亲和力低于纳摩尔，对神经节α 3 <$4亚型的选择性大于104倍。在药理学上，沙泽替丁-A是一种非常新颖的“沉默脱敏剂”。它使a4 <$2 nAChR脱敏而不激活它们，并使它们保持在脱敏状态。功能测定显示，沙泽替丁-A，与伐尼克兰相反，不显示激动剂活性的α 4 <$2或α 3 <$4 nAChR亚型。值得注意的是，在动物身上的初步研究表明，它也有尼古丁样的辨别刺激作用。有了这种独特的先导化合物，我们希望有机会更详细地研究沙泽替丁-A的SAR。本研究的目标是：（1）在前期研究的基础上，设计合成一系列sazetidine-A类似物;（2）检测其与一系列nAChR亚型的结合和功能;（3）筛选出最有希望的类似物用于尼古丁辨别动物实验。理想情况下，这项工作将导致新的α 4 <$2亚型选择性烟碱配体的开发，用于戒烟治疗。