Searching for Novel Analgesic and Anti-inflammatory Agents

描述（由申请人提供）：该R03 （ECHEM）申请计划探索新策略以加速寻找新型镇痛和抗炎药的进展。在过去的几十年里，镇痛和抗炎药的研究一直是医学和制药科学中最活跃的课题之一。到目前为止，市场上几乎所有已知的镇痛和抗炎药物都已被证明具有生理作用，如脊柱上镇痛、呼吸抑制、瞳孔缩小、欣快感、恶心和胃肠道运动减少。这些不良影响给世界各地的许多病人及其家属造成了严重的医疗问题。寻找新的药剂，特别是那些简洁的小分子的药剂仍然是重要的和具有挑战性的。本文设计并合成了一系列新型N-a、a-环酰基甘氨酸和乙醇酰胺的文库，以控制它们的结构灵活性，最大限度地提高它们的结合亲和力和生物活性。同时，还将合成新的n -酰基甘氨酸和乙醇酰胺模拟物的手性氨基醇和二胺及其文库。PI小组发明的新型手性n -膦亚胺化学将用于合成b-羟基a-氨基酸和1-羟基邻氨基醇，它们是n -花生四烯醇基乙醇酰胺的前体。此外，还将研究不对称二胺化反应，以不对称合成a、a-二胺酸和相应的1-羟基邻二胺。由此产生的新型镇痛和抗炎药的药理学特征将被评估。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名本科生在PI上发表了研究论文。这些学生大多顺利进入医学院。目前的NIH-R03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。自1968年以来，马萨诸塞大学医学院的萨姆纳·伯斯坦教授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，结果发现了四氢大麻酚（THC）的氧化代谢途径。该途径的最终产物是THC-11-oic酸，它作为模板发现了一种合成类似物，阿甲酸，一种有效的镇痛和抗炎药，大大降低了精神活性。阿菊酸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，例如二十烷类花生四烯醇乙醇酰胺。一种类似物，或可能的代谢物，n -花生四烯酰基甘氨酸（NAGly）被发现，导致进一步发现一个酰基氨基酸类似物家族。这些被称为elmiric酸的分子已被证明具有作为新型抗炎剂的潜力。项目负责人和联合项目负责人在这个问题上的经验使这个拨款建议是可行的。公共卫生相关性：该提案计划寻找新的镇痛和抗炎剂，以潜在地取代已经使用了很长时间的传统药物。创新策略包括使用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，或至少减少不良影响，如成瘾，呼吸抑制，药物依赖和许多其他相关的副作用，存在于所有已知的药物。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。所有研究生和20多名本科生在PI上发表了研究论文。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拨款将大大有利于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领域。

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.