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 employs 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM087316-05A1
Application #
8758310
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Ge, Rile; Pejo, Ervin; Gallin, Hilary et al. (2014) The pharmacology of cyclopropyl-methoxycarbonyl metomidate: a comparison with propofol. Anesth Analg 118:563-7
Pejo, Ervin; Santer, Peter; Jeffrey, Spencer et al. (2014) Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology. Anesthesiology 121:290-301
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
Desai, Rooma; Miller, Keith W; Raines, Douglas E (2013) The pyrrole etomidate analog carboetomidate potently inhibits human 5-HT3A receptor function: comparisons with etomidate and potential implications for emetogenesis. Anesth Analg 116:573-9
Ge, Rile; Pejo, Ervin; Cotten, Joseph F et al. (2013) Adrenocortical suppression and recovery after continuous hypnotic infusion: etomidate versus its soft analogue cyclopropyl-methoxycarbonyl metomidate. Crit Care 17:R20
Shanmugasundararaj, Sivananthaperumal; Zhou, Xiaojuan; Neunzig, Jens et al. (2013) Carboetomidate: an analog of etomidate that interacts weakly with 11*-hydroxylase. Anesth Analg 116:1249-56
Pejo, Ervin; Feng, Yan; Chao, Wei et al. (2012) Differential effects of etomidate and its pyrrole analogue carboetomidate on the adrenocortical and cytokine responses to endotoxemia. Crit Care Med 40:187-92
Pejo, Ervin; Ge, Rile; Banacos, Natalie et al. (2012) Electroencephalographic recovery, hypnotic emergence, and the effects of metabolite after continuous infusions of a rapidly metabolized etomidate analog in rats. Anesthesiology 116:1057-65
Pierce, David W; Pejo, Ervin; Raines, Douglas E et al. (2012) Carboetomidate inhibits alpha4/beta2 neuronal nicotinic acetylcholine receptors at concentrations affecting animals. Anesth Analg 115:70-2
Cotten, Joseph F; Le Ge, Ri; Banacos, Natalie et al. (2011) Closed-loop continuous infusions of etomidate and etomidate analogs in rats: a comparative study of dosing and the impact on adrenocortical function. Anesthesiology 115:764-73

Showing the most recent 10 out of 11 publications