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A newly developed anesthetic based on a unique chemical core.

ABSTRACT: Intravenous anesthetic agents are associated with cardiovascular instability and poorly tolerated in patients with cardiovascular disease, trauma, or acute systemic illness. We hypothesized that a new class of intravenous (IV) anesthetic molecules that is highly selective for the slow type of ?-aminobutyric acid type A receptor (GABA_AR) could have potent anesthetic efficacy with limited cardiovascular effects. Through in silico screening using our GABA_AR model, we identified a class of lead compounds that are N-arylpyrrole derivatives. Electrophysiological analyses using both an in vitro expression system and intact rodent hippocampal brain slice recordings demonstrate a GABA_AR-mediated mechanism. In vivo experiments also demonstrate overt anesthetic activity in both tadpoles and rats with a potency slightly greater than that of propofol. Unlike the clinically approved GABAergic anesthetic etomidate, the chemical structure of our N-arylpyrrole derivative is devoid of the chemical moieties producing adrenal suppression. Our class of compounds also shows minimal to no suppression of blood pressure, in marked contrast to the hemodynamic effects of propofol. These compounds are derived from chemical structures not previously associated with anesthesia and demonstrate that selective targeting of GABA_AR-slow subtypes may eliminate the hemodynamic side effects associated with conventional IV anesthetics.

SUBMITTER: Cayla NS

PROVIDER: S-EPMC6681746 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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A newly developed anesthetic based on a unique chemical core.

Cayla Noëlie S NS Dagne Beza A BA Wu Yun Y Lu Yao Y Rodriguez Larry L Davies Daryl L DL Gross Eric R ER Heifets Boris D BD Davies M Frances MF MacIver M Bruce MB Bertaccini Edward J EJ

Proceedings of the National Academy of Sciences of the United States of America 20190715 31

Intravenous anesthetic agents are associated with cardiovascular instability and poorly tolerated in patients with cardiovascular disease, trauma, or acute systemic illness. We hypothesized that a new class of intravenous (IV) anesthetic molecules that is highly selective for the slow type of γ-aminobutyric acid type A receptor (GABA<sub>A</sub>R) could have potent anesthetic efficacy with limited cardiovascular effects. Through in silico screening using our GABA<sub>A</sub>R model, we identifie ...[more]

PMID: 31308218

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A newly developed anesthetic based on a unique chemical core.

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A newly developed anesthetic based on a unique chemical core.

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