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 ?-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.
There is a great clinical need for safer general anesthetics, particularly for use in the elderly and critically. There is also an important practical need for anesthetics that are ultra-short acting, which would allow faster and more predictable anesthetic recovery after surgery. The proposed research is relevant to the public health because it will lead to the creation of potent new general anesthetics that are safer than existing agents and allow patients to recover more rapidly after surgery.
|McGrath, Megan; Yu, Zhiyi; Jayakar, Selwyn S et al. (2018) Etomidate and Etomidate Analog Binding and Positive Modulation of ?-Aminobutyric Acid Type A Receptors: Evidence for a State-dependent Cutoff Effect. Anesthesiology 129:959-969|
|McGrath, Megan; Ma, Celena; Raines, Douglas E (2018) Dimethoxy-etomidate: A Nonhypnotic Etomidate Analog that Potently Inhibits Steroidogenesis. J Pharmacol Exp Ther 364:229-237|
|Ma, Celena; Pejo, Ervin; McGrath, Megan et al. (2017) Competitive Antagonism of Anesthetic Action at the ?-Aminobutyric Acid Type A Receptor by a Novel Etomidate Analog with Low Intrinsic Efficacy. Anesthesiology 127:824-837|
|Pejo, Ervin; Santer, Peter; Wang, Lei et al. (2016) ?-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs. Anesthesiology 124:651-63|
|Pejo, Ervin; Liu, Jifeng; Lin, Xiangjie et al. (2016) Distinct Hypnotic Recoveries After Infusions of Methoxycarbonyl Etomidate and Cyclopropyl Methoxycarbonyl Metomidate: The Role of the Metabolite. Anesth Analg 122:1008-14|
|Pejo, Ervin; Zhou, Xiaojuan; Husain, S Shaukat et al. (2016) Sedative-hypnotic Binding to 11?-hydroxylase. Anesthesiology 125:943-951|
|Santer, Peter; Pejo, Ervin; Feng, Yan et al. (2015) Cyclopropyl-methoxycarbonyl Metomidate: Studies in a Lipopolysaccharide Inflammatory Model of Sepsis. Anesthesiology 123:368-76|
|Raines, Douglas E (2015) The pharmacology of etomidate and etomidate derivatives. Int Anesthesiol Clin 53:63-75|
|Campagna, Jason A; Pojasek, Kevin; Grayzel, David et al. (2014) Advancing novel anesthetics: pharmacodynamic and pharmacokinetic studies of cyclopropyl-methoxycarbonyl metomidate in dogs. Anesthesiology 121:1203-16|
|Ge, Rile; Pejo, Ervin; Gallin, Hilary et al. (2014) The pharmacology of cyclopropyl-methoxycarbonyl metomidate: a comparison with propofol. Anesth Analg 118:563-7|
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