Etomidate Analogues as Safer General Anesthetics

仅在美国，每天就有近10万名患者接受全身麻醉。不幸的是，所有的麻醉剂 产生严重的副作用，特别是在老年人和危重病人。大多数也被慢慢淘汰， 导致延迟的麻醉恢复，甚至在年轻的健康患者中也是如此。理想的麻醉剂是 高效，超短效（与上下文无关的恢复时间），没有危险的副作用。 这个转化研究项目的长期目标是建立战略，将导致 开发更接近理想的麻醉剂。在第一次融资期间，我们开发了 依托咪酯的新类似物，其分别为（1）高效麻醉剂，（2）超短效，或（3） 完全没有肾上腺皮质毒性然而，没有类似物拥有所有这三个所需的 质量，和一些意外产生的代谢产物具有足够的药理活性，以延迟 复苏这次竞争性更新的目标是，我们追求目标的下一步，是建立 麻醉剂和代谢物的结构-活性关系，并测试新的策略，使我们能够 联合收割机将所有三种理想的特性结合成一种药物， 上维护我们的一般方法是使用临床麻醉剂依托咪酯和实验麻醉剂 TG 41作为先导化合物。这两种咪唑羧酸盐是极好的新线索， 药物，因为它们比其他已知的麻醉剂更有效和选择性， 治疗指标在TG 41的情况下，我们的初步研究表明，它也缺乏 严重限制依托咪酯使用的肾上腺皮质毒性。我们的核心假设是， 单独增加麻醉效力，缩短作用持续时间，消除肾上腺皮质功能 毒性或降低代谢物效力可以合理地组合到这些先导物中，以产生接近理想的 麻醉剂在大量已发表的研究和强有力的初步数据的指导下，我们将对此进行测试。 通过追求四个具体目标：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）为了检验以下假设： 我们在体内观察到的依托咪酯代谢物的药理学作用源于它们不带电荷， 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;和4）定义TG 41的药理学， 开发快速代谢、超短效TG 41类似物。这项研究具有很强的创新性 因为它采用的新策略，合理地设计新的全身麻醉药， 药理学特性这项研究具有重要意义，因为它将导致更好的发展， 满足重要且不断增长的患者需求的麻醉剂。

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.