Etomidate Analogues as Safer General Anesthetics

依托咪酯类似物作为更安全的全身麻醉药

• 批准号: 8758310
• 负责人: DOUGLAS E RAINES
• 金额: $ 37.97万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758310
• 关键词: Achievement; Address; Administrator; Adverse effects; Anesthesia procedures; Anesthetics; Animal Model; Award; Birds; Boston; Budgets; Buffers; Businesses; Carboxylic Acids; Cardiovascular system; Cells; Client satisfaction; Computer Simulation; Confidential Information; Critical Illness; Data; Direct Costs; Documentation; Elderly; Electronic Mail; Esters; Etomidate; Funding; General Anesthesia; General anesthetic drugs; Goals; Grant; Guidelines; Health Care Costs; Human Resources; Huntington Disease; Hydrocortisone; IACUC; Imidazole; Institution; Language; Lead; Letters; Mails; Mental Depression; Methods; Modeling; Molecular; Molecular Structure; National Institute of General Medical Sciences; Operating Rooms; Operative Surgical Procedures; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Plague; Procedures; Property; Public Health; Reader; Reading; Recovery; Reporting; Research; Research Project Grants; Sampling; Series; Side; Specialist; Structure-Activity Relationship; Telefacsimile; Telephone; Testing; Text; Therapeutic Index; Toxic effect; Translational Research; Travel; United States National Institutes of Health; Ventilatory Depression; Work; abstracting; analog; carboxylate; clinical practice; comparative; design; halogenation; improved; in vivo; lipophilicity; literate; meetings; new technology; novel; pharmacophore; public health relevance; receptor; response

In the U.S. alone, nearly 100,000 patients each day receive general anesthesia. Unfortunately, all anesthetics produce serious side effects, particularly in the elderly and critically ill. Most are also eliminated slowly, resulting in delayed anesthetic recovery even in young healthy patients. The ideal anesthetic agent would be highly potent, ultra-short acting (with a context-insensitive recovery time), and without dangerous side effects. The long-term goal of this translational research project is to establish strategies that will lead to the development of anesthetic agents that are closer to the ideal. During the first funding period, we developed novel analogues of etomidate that individually were (1) highly potent anesthetics, (2) ultra-short acting, or (3) completely devoid of adrenocortical toxicity. However, no analogue possessed all three of these desired qualities, and some unexpectedly produced metabolites with sufficient pharmacological activity to delay recovery. The objective of this competitive renewal, which is our next step in pursuit of our goal, is to establish anesthetic and metabolite structure-activity relationships and to test new strategies that will allow us to combine all three desirable properties into a single drug that can be used for both anesthetic induction and maintenance. Our general approach is to use the clinical anesthetic etomidate and the experimental anesthetic TG41 as lead compounds. These two imidazole-carboxylates are excellent new leads upon which to base new drugs because they are more potent and selective than other known anesthetics and have unusually high therapeutic indices. In the case of TG41, our preliminary studies show that it is also devoid of the adrenocortical toxicity that severely limits etomidate use. Our central hypothesis is that specific molecular modifications that individually increase anesthetic potency, shorten duration of action, abolish adrenocortical toxicity, or reduce metabolite potency can be rationally combined into these leads to produce a near-ideal anesthetic agent. Guided by substantial published research and strong preliminary data, we will test this hypothesis by pursuing four specific aims: 1) to define structure-activity relationships for rapidly metabolized etomidate analogues (“etomidate esters”) with varying side chains; (2) to test the hypothesis that the pharmacological actions of etomidate ester metabolites that we observe in vivo arise from their uncharged, protonated fraction; 3) to build pharmacophore models that can explain and predict the GABAA receptor potencies and β-subunit selectivities of etomidate analogues; and 4) to define the pharmacology of TG41 and to develop rapidly metabolized, ultra-short acting TG41 analogues. The proposed research is highly innovative because it employ’s novel strategies to rationally design new general anesthetics with specific, desirable pharmacological properties. The proposed research is significant because it will lead to the development of better anesthetics that meet important – and growing – patient needs.

仅在美国，每天就有近10万名患者接受全身麻醉。不幸的是，所有麻醉剂 产生严重的副作用，特别是对老年人和危重病人。大多数也会慢慢被淘汰， 导致麻醉恢复延迟，即使是年轻的健康患者也是如此。理想的麻醉剂应该是 高效、超短的表演(与上下文无关的恢复时间)，并且没有危险的副作用。 这个翻译研究项目的长期目标是建立战略，以导致 开发更接近理想的麻醉剂。在第一个资助期，我们开发了 依托咪酯的新类似物，分别是(1)高效麻醉药，(2)超短效，或(3) 完全没有肾上腺皮质毒性。然而，没有一种类似物拥有所有这三种所需的东西。 质量，以及一些意外产生的具有足够药理活性的代谢物 恢复。这次竞争性更新的目标，也是我们追求目标的下一步，是为了建立 麻醉剂和代谢物的构效关系，并测试新的策略，使我们能够 将所有这三种理想的特性组合成一种药物，既可用于麻醉诱导，也可用于 维修。我们的一般做法是使用临床麻醉剂依托咪酯和实验麻醉剂 TG41为先导化合物。这两个咪唑-羧酸盐是很好的新的基础上的新的线索 药物，因为它们比其他已知的麻醉药更有效和更有选择性，而且具有异常高的 治疗指标。在TG41的情况下，我们的初步研究表明，它也没有 肾上腺皮质毒性，严重限制依托咪酯的使用。我们的中心假设是特定的分子 个别增加麻醉效力、缩短作用时间、取消肾上腺皮质激素的修改 毒性，或降低代谢物的效力，可以合理地组合到这些引线中，产生一种近乎理想的 麻醉剂。在大量已发表的研究和强大的初步数据的指导下，我们将检验这一点 通过追求四个具体目标进行假设：1)定义快速代谢的结构-活性关系 具有不同侧链的依托咪酯类似物(“依托咪酯”)；(2)检验假设 我们在体内观察到的依托咪酯代谢物的药理作用来自于它们的无电荷， 质子化部分；3)建立能够解释和预测GABAA受体的药效团模型 依托咪酯类似物的效力和β亚基选择性；以及4)确定TG41和TO的药理作用 开发快速代谢、超短效的TG41类似物。建议的研究具有很高的创新性。 因为它采用了新的策略，合理地设计出具有特定、可取的新的全身麻醉药 药理特性。这项拟议的研究具有重要意义，因为它将导致更好的 满足重要的和不断增长的患者需求的麻醉药。