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Research at Mass General
Principal Associate in Anesthesia, Harvard Medical School
One area of my research focuses on elucidation of molecular mechanism of general anesthesia. The state of general anesthesia is produced by a highly diverse group of agents. The prevailing view is that these agents elicit their action by interacting with protein molecules, especially those belonging to the ligand-gated ion channel superfamily of receptors, which include GABAA, glycine, nicotonic acetylcholine and 5HT3 receptors. My research objective is to delineate the site of interaction of various classes of general anesthetics, especially long chain alcohols and etomidate with target proteins using photoactivatable analogs of these anesthetics. This has been a collaborative effort with Professor Keith Miller at the Department of Anesthesia, Massachusetts General Hospital and Professor Jonathan Cohen at the Department of Neurobiology, Harvard Medical School. Our joint efforts for more than a decade has led to the development of a variety of photoreactive general anesthetic probes that has culminated in localizing the binding sites of these anesthetics with acetylcholine receptor, GABAA receptor and a variety of other target proteins.The focus of another area of my research is the development of etomidate derivatives that retain the desirable anesthetic qualities of the parent molecule but do not cause the undesirable suppression of adrenocortical function. Etomidate is a rapidly acting intravenous general anesthetic that differs from other induction agents by its ability to maintain hemodynamic stability, even in the setting of cardiovascular compromise. It has consequently emerged as an agent of choice in critically ill patients. However, etomidate also causes an undesirable side effect: It is a potent inhibitor of 11- hydroxylase, the enzyme involved in the biosynthesis of cortisol. This inhibitory action leads to prolonged depletion of cortisol that can last for several days after administration of etomidate is stopped. One approach to minimize the suppression of adrenocortical function is to develop ultra-rapidly metabolized derivatives of etomidate that maintain hemodynamic stability without causing prolonged inhibition of cortisol synthesis. I have been involved in the development of such analogues of etomidate in collaboration with Dr. Douglas Raines. With my background as PhD in the areas of organic chemistry and biochemistry and that of Dr Rianes’ expertise as a clinical anesthesiologist, our research pursuit has been highly productive and has led to discovery of exciting new analogues of etomidate with potential of being useful general anesthetic agents.
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