Searching for Novel Analgesic and Anti-inflammatory Agents

寻找新型镇痛抗炎药物

• 批准号: 7697784
• 负责人: Guigen Li
• 金额: $ 19.77万
• 依托单位: TEXAS TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7697784
• 关键词: Absence of pain sensation; Acids; Adverse effects; Affinity; Amino Acids; Amino Alcohols; Analgesics; Anti Inflammatory Analgesics; Anti-Inflammatory Agents; Applications Grants; Area; Binding; Biological; Cannabinoids; Chemistry; Constitutional; Diamines; Drug Addiction; Eicosanoids; Endocannabinoids; Euphoria; Family; Gastrointestinal Motility; Glycine; Graduate Education; Grant; Isomerism; Libraries; Marketing; Massachusetts; Medical; Meiosis; Metabolic Pathway; Metabolism; Nausea; New Agents; Occupations; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Principal Investigator; Publications; Reaction; Research; Science; Series; Students; Tetrahydrocannabinol; Texas; Time; Training; Universities; Ventilatory Depression; Work; addiction; ajulemic acid; analog; anandamide; chronic pain; design; experience; flexibility; innovation; medical schools; mimetics; novel; novel strategies; professor; programs; public health relevance; small molecule; therapy development

DESCRIPTION (provided by applicant): This R03 (ECHEM) proposal plans to explore novel strategies to accelerate the progress of searching for novel analgesic and anti-inflammatory agents. It is known that research on analgesic and anti-inflammatory agent has been among the most active topics in medicinal and pharmaceutical sciences in the past several decades. So far, nearly all of known analgesic and anti-inflammatory agents on the market have been proven to show physiological effects, such as supraspinal analgesia, respiratory depression, miosis, euphoria, nausea, and reduced gastrointestinal motility. These undesirable effects have resulted in serious medical problems for numerous patients and their families worldwide. The search for new agents, particularly, for those of concise and small molecules still remains important and challenging. In this proposal libraries consisting a series of novel N-a,a-cyclic acyl glycines and ethanolamides, N-acyl a,a-cyclic glycines and cyclic ethanolamides have been designed and will be synthesized so as to control their structural flexibility and to maximize their binding affinities and biological activities. Meanwhile, new chiral amino alcohols and diamines for N-acyl glycine and ethanolamide mimetics as well as their libraries will be synthesized. The novel chiral N-phosphonimine chemistry invented by the PI's group will be employed for the synthesis of b-hydroxy a-amino acids and 1-hydroxy vicinal amino alcohols that are precursors of N-arachiodonoyl ethanoamides. In addition, the asymmetric diamination reaction will be studied for asymmetric synthesis of a,a-diamino acids and corresponding 1-hydroxy vicinal diamines. The pharmacological profiles of resulting novel analgesic and anti-inflammatory agents will be evaluated. The PI's group has trained nearly 50 undergraduate students and 14 graduates for conducting organic and bioorganic research. All graduates and 25 of undergraduates achieved research publications with the PI. Most of these students successfully entered medical schools. The present NIH-R03 project will greatly benefit the PI's undergraduates and graduate education at Texas Tech University. The co-PI, Professor Sumner Burstein at University of Massachusetts Medical School has been working in the area of cannabinoids since 1968. His efforts were originally focused on the metabolism of cannabinoids and resulted in the discovery of the oxidative metabolic pathway of tetrahydrocannabinol (THC). The terminal product of this pathway is THC-11-oic acid, which has served as a template for the discovery of a synthetic analog, ajulemic acid, a potent analgesic and anti-inflammatory agent with greatly reduced psychotropic activity. Ajulemic acid is currently undergoing commercial development for the treatment of chronic pain. Most recently, the co-PI has been working in the area of the endogenous cannabinoids exemplified by the eicosanoid arachidonoyl ethanolamide. An analog, or possible metabolite of anandamide, N-arachidonoyl glycine (NAGly), was discovered which led to the further discovery of a family of acyl amino acid analogs. These molecules, called elmiric acids, have been shown to have potential as novel anti-inflammatory agents. The experience of the PI and co-PI on this topic makes this grant proposal feasible. PUBLIC HEALTH RELEVANCE: This proposal plans to find new analgesic and anti-inflammatory agents to potentially replace the traditional drugs that have been used for a long time. Innovative strategies including the use of N- a,a-cyclic acyl glycines and ethanolamides, N-acyl a,a-cyclic glycines and cyclic ethanolamides will be explored. The new candidates can avoid, or at least minimize undesirable effects such as addiction,respiratory depression, drug dependence and many other related side effects that exist in all known drug. Thus far, the PI's group has trained more than 50 undergraduate students and 16 graduates in conducting research in organic/medicinal research. All graduates and more than 20 of undergraduates achieved research publications with the PI. All of these students either successfully entered medical schools or found jobs in pharmaceutical companies. The present NIH-R15 grant will greatly benefit PI's undergraduate and graduate education and help the PI to attract more students into sciences.

描述（由申请人提供）：本R 03（ECHEM）提案计划探索新策略，以加速寻找新型镇痛和抗炎药物的进展。镇痛抗炎药物的研究是近几十年来医药学研究的热点之一。迄今为止，市场上几乎所有已知的镇痛和抗炎剂都已被证明显示出生理作用，如脊髓上镇痛、呼吸抑制、瞳孔缩小、欣快、恶心和胃肠道运动减少。这些不良反应给世界各地的许多患者及其家属带来了严重的医疗问题。寻找新的药物，特别是那些简洁和小分子的药物仍然是重要和具有挑战性的。在该提议中，已经设计并将合成由一系列新的N-α，α-环状酰基甘氨酸和乙醇酰胺组成的文库，N-酰基α，α-环状甘氨酸和环状乙醇酰胺，以控制它们的结构柔性并使它们的结合亲和力和生物活性最大化。同时，还将合成新的N-酰基甘氨酸和乙醇酰胺模拟物的手性氨基醇和氨基二胺及其库。由PI的小组发明的新的手性N-膦亚胺化学将用于合成作为N-花生四烯酸乙醇酰胺的前体的b-羟基α-氨基酸和1-羟基邻位氨基醇。此外，还将研究不对称二胺化反应，用于不对称合成α，α-二氨基酸和相应的1-羟基邻二胺。将评价所得新型镇痛和抗炎剂的药理学特征。PI的小组已经培训了近50名本科生和14名研究生进行有机和生物有机研究。所有研究生和25名本科生都在PI上发表了研究论文。这些学生中的大多数都成功地进入了医学院。目前的NIH-R 03项目将极大地有利于PI在德克萨斯理工大学的本科生和研究生教育。共同PI，马萨诸塞州医学院的Sumner Burstein教授自1968年以来一直在大麻素领域工作。他的努力最初集中在大麻素的代谢上，并发现了四氢大麻酚（THC）的氧化代谢途径。这一途径的最终产物是THC-11-oic acid，它已被用作发现合成类似物阿佳酸（ajulemic acid）的模板，阿佳酸是一种有效的镇痛和抗炎剂，其精神活性大大降低。Ajulemic acid目前正在进行商业开发，用于治疗慢性疼痛。最近，co-PI一直在内源性大麻素领域工作，例如花生四烯酸乙醇酰胺。发现了花生四烯酸酰胺的类似物或可能的代谢物N-花生四烯酸甘氨酸（NAGly），这导致了酰基氨基酸类似物家族的进一步发现。这些被称为榄香酸的分子已被证明具有作为新型抗炎剂的潜力。PI和co-PI在这一主题上的经验使这项赠款提案可行。公共卫生关系：该提案计划寻找新的镇痛和抗炎药物，以取代长期使用的传统药物。将探索包括使用N-α，α-环状酰基甘氨酸和乙醇酰胺、N-酰基α，α-环状甘氨酸和环状乙醇酰胺的创新策略。新的候选药物可以避免或至少最小化不良反应，如成瘾、呼吸抑制、药物依赖和所有已知药物中存在的许多其他相关副作用。到目前为止，PI的小组已经培训了50多名本科生和16名研究生进行有机/医学研究。所有的研究生和20多名本科生都在PI上发表了研究论文。所有这些学生要么成功进入医学院，要么在制药公司找到工作。目前的NIH-R15赠款将大大有利于PI的本科和研究生教育，并帮助PI吸引更多的学生进入科学。