Massachusetts General Hospital

BiographyMy research is focused on understanding the molecular mechanisms of anesthetic action on ligand-gated ion channels. General anesthetics are administered to more than 25 million patients in the U.S each year, but the underlying molecular mechanisms are not understood. Cys-loop ligand-gated ion channels such as the GABAA, 5-HT3, glycine, and nicotinic acetylcholine receptors form a superfamily of anesthetic-sensitive receptors that are thought to play important roles in mediating the desirable clinical actions and undesirable side-effects of general anesthetics. NMDA receptors are glutamatergic ligand-gated ion channels that are also important targets of general anesthetics

My laboratory uses electrophysiological techniques to define the actions of general anesthetics on ligand-gated ion channels. Our recent focus has been on 5-HT3 and NMDA receptors. By applying electrophysiological techniques with very rapid solution exchange, we are measuring 5-HT3 receptor activation, deactivation, and desensitization rates and then using computer kinetic modeling to understand how these receptors work and what anesthetics do.

Research

Research Areas

• Defining the molecular mechanisms of general anesthetic actionon relevant protein targets: GABAA receptors, NMDA receptors, Serotonin receptors, 11beta-hydroxylase
• Rationally designing new anesthetic etomidate analogues
• Studying the pharmacology of our new drugs in receptor, cellular, and rodent models

Description of Research

The main goal of my research lab is to gain a better understanding of how and where general anesthetics act at the molecular and receptor levels in order to build up a pharmacological and mechanistic basis for rationally designing new anesthetic agents. To achieve this goal, we use medicinal chemical, biophysical, electrophysiological, and computational approaches.  Much of our current effort focuses on etomidate, an intravenous anesthetic that provides superior hemodynamic stability, but is slowly metabolized and potently inhibits 11beta-hydroxylase. This leads to profound and persistent adrenocortical suppression that is potentially deadly, particularly in the critically ill. We are designing and synthesizing novel analogues of etomidate with reduced capacity to suppress adrenocortical function, studying these agents using computer modeling, in vitro receptor and cellular systems, and rodent models. We have designed some of these agents to be ultra-rapidly metabolized by nonspecific esterases and very short-acting, similar to remifentanil and esmolol. We have designed others not to bind to 11beta-hydroxylase. Additional details of this aspect of our work can be found in recent published reviews (e.g. Br J Anaesth. 2010 Sep;105(3):246-54 and Chemical & Engineering News 2011 Aug;89(34):13-20).

In collaboration with Dr. Fumito Ichinose, the lab is also developing and studying novel drugs to prevent or treat neurological disorders, including ischemic stroke and dementia. These drugs are designed to both inhibit NMDA receptors and release hydrogen sulfide gas.

PublicationsView publications

Mass. General team develops potentially safer general anesthetic