Douglas Raines, M.D.
Physician Investigator (Cl)
Anes. Research - Monthly, Research Institute
Edward Mallinckrodt, Jr. Professor of Anaesthesia in the Field Pharmacology and Innovation
Harvard Medical School
Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital
|MD University of Virginia School of Medicine 1987|
- Defining the molecular mechanisms of general anesthetic action on 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.