Novel Tobacco Cessation Agents

新型戒烟剂

• 批准号: 9171351
• 负责人: John P Harrelson
• 金额: $ 37.51万
• 依托单位: PACIFIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171351
• 关键词: 7alpha hydroxylase; Address; Adverse effects; Affinity; Aldehydes; Binding; Biological Assay; Cessation of life; Cigarette; Cinnamon - dietary; Complex; Computer software; Cytochrome P450; Cytosol; Depressed mood; Development; Disease; Dose; Drug Kinetics; Enrollment; Enzymes; Evaluation; Family; Food Industry; Future; Goals; Half-Life; Health; Hepatocyte; Hepatotoxicity; Human; Hypertension; In Vitro; Interdisciplinary Study; Investigation; Knowledge; Lead; Liver Microsomes; Mass Spectrum Analysis; Measures; Mental Depression; Metabolism; Minor; Molecular Models; Mus; Natural Products; Nicotine; Oral; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacy Students; Protein Isoforms; Recombinants; Research; Research Infrastructure; Research Training; Risk; Role; Self Destructive Behavior; Smoke; Smoker; Smoking; Smoking Behavior; Source; Spectrum Analysis; Structure; Targeted Research; Time; Tobacco Dependence; Tobacco Use Cessation; Toxic effect; Toxicology; Translating; Universities; Weaning; Work; absorption; addiction; analog; base; cinnamic aldehyde; design; drug candidate; drug development; drug discovery; drug market; effective therapy; improved; in vitro testing; in vivo; inhibitor/antagonist; interpatient variability; molecular modeling; multidisciplinary; novel; pharmacokinetic characteristic; prototype; research study; response; smoking cessation; suicidal behavior; therapeutic target; training opportunity; translational study; undergraduate student

Tobacco addiction is the leading cause of preventable death and is predicted to contribute to more than 8 million deaths worldwide per year by 2030. Despite the impact of this addiction on human health, smoking cessation is a challenge for many, at least in part because addiction is a complex, multifactorial disease with few pharmacological treatments available. It has been shown that extending the half-life of nicotine through decreased metabolism alters human smoking behavior, resulting in fewer cigarettes smoked per day, decreased smoking intensity, and improved smoking cessation rates. Our preliminary results indicate that cinnamic aldehyde, a natural product from cinnamon used extensively in the food industry, is an irreversible inhibitor of the human nicotine metabolizing enzyme, cytochrome P450 2A6 (CYP2A6), which is responsible for metabolizing 70-90% of a nicotine dose. With three specific aims, this project will investigate cinnamic aldehyde as a prototype for the design of new orally administered tobacco cessation agents, with a unique mechanism of action that will improve smoking cessation rates with limited risk for toxicity. Using a combination of fluorescent assays, mass spectrometry, and absorption spectroscopy, Specific Aim 1 evaluates the selectivity, potency, and mechanism for inhibition of human CYP2A6 by cinnamic aldehdye in human liver microsomes, cytosol, and recombinant human enzymes. This analysis will reveal details about the type of structural changes necessary to generate more potent and selective inhibitors. Using molecular modeling, fluorescent assays, and spectral binding studies, Specific Aim 2 evaluates structural analogs of cinnamic aldehyde for their capacity to selectively bind to and inhibit human CYP2A6. The findings from this aim will focus on identifying agents for further investigation as viable drugs. In Specific Aim 3, the `druggability' of cinnamic aldehyde and structural analogs will be evaluated as tobacco cessation agents, ultimately in cryopreserved human hepatocytes. These compounds will also be evaluated for toxicity and pharmacokinetic factors, such as compound stability. This project represents the first known attempt to use the cinnamic aldehyde structure as a prototype from which to design novel smoking cessation agents, which is a long-term goal of this research. Describing the agents' pharmacokinetic characteristics is an essential step for translating selective in vitro inhibitors to viable drug candidates. Thus, if the results from this work support our hypothesis, it will lay the groundwork for future translational studies, which would evaluate the degree to which the agents inhibit nicotine metabolism in vivo, for example in mice, which also utilize CYP2A for nicotine metabolism. This work will also advance our knowledge of how aldehyde-containing agents inhibit cytochrome P450 enzymes, a large family of enzymes from which several isoforms are therapeutic targets. This R15 application offers excellent interdisciplinary research training opportunities for undergraduate and pharmacy students, and will significantly enhance the research infrastructure at Pacific University.

烟草成瘾是可预防死亡的主要原因，预计将导致超过 8 到 2030 年，全球每年将有 100 万人死亡。尽管吸烟对人类健康有影响，但 戒烟对许多人来说是一个挑战，至少部分是因为成瘾是一种复杂的、多因素的疾病， 可用的药物治疗很少。研究表明，通过延长尼古丁的半衰期 新陈代谢的降低会改变人类的吸烟行为，导致每天吸烟的数量减少， 降低吸烟强度，提高戒烟率。我们的初步结果表明 肉桂醛是肉桂的天然产物，广泛用于食品工业，是一种不可逆的 人类尼古丁代谢酶细胞色素 P450 2A6 (CYP2A6) 的抑制剂，该酶负责 代谢 70-90% 的尼古丁剂量。该项目将研究肉桂酸的三个具体目标 醛作为设计新型口服戒烟剂的原型， 独特的作用机制将提高戒烟率，同时毒性风险有限。 结合使用荧光测定、质谱和吸收光谱，具体目标 1 评估肉桂醛对人 CYP2A6 的选择性、效力和抑制机制 人肝微粒体、细胞质和重组人酶。该分析将揭示有关的详细信息 产生更有效和选择性抑制剂所需的结构变化类型。使用分子 建模、荧光测定和光谱结合研究，Specific Aim 2 评估结构类似物 肉桂醛具有选择性结合并抑制人 CYP2A6 的能力。由此得出的结论 目标将侧重于确定作为可行药物进行进一步研究的药物。在具体目标 3 中， 肉桂醛和结构类似物的“成药性”将作为戒烟剂进行评估， 最终在冷冻保存的人肝细胞中。还将评估这些化合物的毒性和 药代动力学因素，例如化合物稳定性。该项目代表了已知的首次尝试使用 以肉桂醛结构为原型设计新型戒烟剂， 本研究的一个长期目标。描述药物的药代动力学特征是重要的一步 用于将选择性体外抑制剂转化为可行的候选药物。因此，如果这项工作的结果支持 我们的假设，它将为未来的转化研究奠定基础，这将评估程度 这些药物可抑制尼古丁体内代谢，例如小鼠体内的尼古丁代谢，小鼠也利用 CYP2A 来代谢尼古丁 代谢。这项工作还将增进我们对含醛试剂如何抑制细胞色素的了解 P450 酶是一个酶大家族，其中的几种亚型是治疗靶点。这个R15 应用程序为本科生和药学提供了极好的跨学科研究培训机会 学生，并将显着增强太平洋大学的研究基础设施。