Searching for Novel Analgesic and Anti-inflammatory Agents

描述(由申请人提供)：这份R03(EChem)提案计划探索新的策略，以加快寻找新的止痛和抗炎药物的进程。众所周知，在过去的几十年里，镇痛和抗炎药物的研究一直是医药科学中最活跃的课题之一。到目前为止，市场上已知的几乎所有的止痛药和抗炎药都被证明具有生理作用，如脊髓上止痛、呼吸抑制、收缩、兴奋、恶心和胃肠动力减慢。这些不良影响给世界各地的许多患者及其家属带来了严重的医疗问题。寻找新的试剂，特别是那些简洁和小分子的试剂，仍然是重要的和具有挑战性的。在这个建议中，我们设计并合成了一系列新的N-a，a-环酰基甘氨酸和乙醇酰胺、N-酰基a，a-环甘氨酸和环乙醇酰胺的文库，以控制它们的结构灵活性，并最大限度地提高它们的结合亲和力和生物活性。同时，还将合成用于N-酰基甘氨酸和乙醇胺类化合物的新型手性氨基醇和二胺及其文库。由Pi‘s小组发明的新型手性N-膦酰亚胺化学将被用于合成N-花生六烷基乙酰胺的前体b-羟基a-氨基酸和1-羟基邻氨基醇。此外，还将研究不对称二氨基化反应，用于不对称合成α，α-二氨基酸和相应的1-羟基邻二胺。将对产生的新型止痛剂和抗炎药的药理学概况进行评估。PI的团队已经培训了近50名本科生和14名毕业生进行有机和生物有机研究。所有毕业生和25名本科生都在PI发表了研究论文。这些学生中的大多数都成功进入了医学院。目前的NIH-R03项目将极大地造福于PI的本科生和德克萨斯理工大学的研究生教育。这位合作者是马萨诸塞大学医学院的萨姆纳·伯斯坦教授，自1968年以来一直致力于大麻类药物的研究。他最初致力于大麻类化合物的代谢，并最终发现了四氢大麻酚(THC)的氧化代谢途径。这个途径的最终产物是THC-11-OIC酸，它是发现一种合成类似物的模板，它是一种有效的止痛和抗炎药物，但精神活性大大降低。阿魏酸目前正在进行商业开发，用于治疗慢性疼痛。最近，该合作小组一直在研究以二十烷基花生四烯基乙醇胺为代表的内源性大麻素。一种类似的或可能的代谢物-N-花生四烯基甘氨酸(NAGLY)被发现，这导致了一类酰基氨基酸类似物的进一步发现。这些分子被称为榄香酸，已被证明具有作为新型抗炎剂的潜力。私人投资和共同投资在这一主题上的经验使这一赠款建议具有可行性。与公共健康相关：这项提案计划寻找新的止痛剂和消炎剂，以潜在地取代长期使用的传统药物。将探索创新战略，包括使用N-a、a-环酰基甘氨酸和乙醇酰胺、N-酰基a、a-环甘氨酸和环乙醇酰胺。新的候选药物可以避免或至少最大限度地减少不良反应，如成瘾、呼吸抑制、药物依赖和许多其他相关的副作用，这些副作用存在于所有已知的药物中。到目前为止，PI的团队已经培训了50多名本科生和16名毕业生进行有机/药物研究。所有毕业生和20多名本科生都在PI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了工作。目前的NIH-R15资助将极大地有利于PI的本科生和研究生教育，并有助于PI吸引更多的学生进入科学。

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.