Syed Shaukat Husain, PhD

Overview

Principal Associate in Anesthesia, Harvard Medical School

Research Areas

• Elucidation of molecular mechanism of general anesthesia using photoactivatable analogues of general anesthetics
• Development of etomidate derivatives that retain the desirable anesthetic qualities of the parent molecule but do not cause the undesirable suppression of adrenocortical function
• Development of ultra-rapidly metabolized derivatives of etomidate that maintain hemodynamic stability without causing prolonged inhibition of cortisol synthesis

Description of Research

One area of my research focuses on elucidation of the 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-b 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.

Publications

Husain SS, Stewart D, Desai R, Hamouda AK, Li SG, Kelly E, Dostalova Z, Zhou X, Cotten JF, Raines DE, Olsen RW, Cohen JB, Forman SA, Miller KW. p-:A Potent Photoreactive General Anesthetic Trifluorodiazirinyl-etomidate Derivative of Etomidate That is Selective for Ligand-Gated Cationic Ion Channels J. Med. Chem  2010, 53, 6432–6444

Hamouda AK, Stewart DS, Husain SS, Cohen JB.: Multiple transmembrane binding sites for p-trifluoromethyldiazirinyl-etomidate, a photoreactive Torpedo nicotinic acetylcholine receptor allosteric inhibitor. J. Biol. Chem  2011; 286: 20466–20477.

Shanmugasundararaj S, Lehle S, Yamodo HI, Husain SS, Tseng C, Nguyen K, Addona GH, Miller KW.The location and nature of general anesthetic binding sites on the active conformation of firefly luciferase: a time resolved photolabeling study.PLoS One. 2012, 7, e29854.

Cotten JF, Le Ge R, Banacos N, Pejo E, Husain SS, Williams JH, Raines DE.Closed-loop continuous infusions of etomidate and etomidate analogs in rats: a comparative study of dosing and the impact on adrenocortical function.Anesthesiology. 2011,115, 764-773.

Pejo E., Ge R., Banacos, N., Cotten JF., Banacos N, Husain SS, Raines DE.Electroencephalographic Recovery, Hypnotic Emergence, and the Effets of Metabolite After Continuous Infusions of a Rapidly Metabolized Etomidate Analog in Rats.  Anesthesiology. May 2012, 116, 1057-1065.

Husain SS, Pejo E., Ge R, Raines DE.Modifying Methoxycarbonyl Etomidate Inter-Ester Spacer Optimizes In Vitro Metabolic Stability and In Vivo Hypnotic potency and Duration of Action.Anesthesiology, November 2012

Ge R., Pejo, E Husain SS, Cotton JF, Raines DE.Electroencephalographic and Hypnotic Recoveries Following Brief and Prolonged Infusions of Etomidate  and optimized Soft.Etomidate  Analogs in Rats. Anesthesiology, November 2012.