Discovery and Mechanism of Novel General Anesthetics Targeting GABAA Receptors

Summary GABAA receptors are pentameric ligand-gated ion channels that mediate most fast inhibitory neurotransmission in the brain. These receptors are essential in the regulation of excitatory signals and their dysfunction can lead to neurological disorders and mental illnesses. Their crucial roles in human health have made GABAA receptors popular targets for a variety of drugs and therapeutics such as general anesthetics. The most widely used intravenous (IV) general anesthetic is propofol, which acts as a positive allosteric modulator (PAM) of GABAA receptors. In patients with risks of cardiovascular or respiratory depression, another PAM called etomidate is often used instead. Although these IV general anesthetics work well, they often cause adverse drug reactions such as airway obstruction and vasodilation induced hypothermia. These adverse reactions can be resolved in the operating room through intubation and patient pre-warming, respectively. Such interventions are inefficient and not practical outside the operating room, for example, in emergency conditions. Therefore, this project aims to discover and characterize novel general anesthetics that are not limited to use in controlled operating room environments. Specifically, I aim to discover GABAA receptor modulators through functional studies, structurally characterize GABAA receptor modulator binding sites, and interrogate mechanisms of potentiation. My proposed functional studies will utilize electrophysiology and leverage drug leads identified through screens performed by collaborators. Concurrently, I aim to determine high resolution structures of GABAA receptors bound to allosteric modulators via single particle cryo-EM. Once modulator binding sites are identified, I plan to define mechanisms of potentiation with functional studies. This work will directly result in modulators with novel mechanisms of general anesthesia that could potentially improve the current anesthetic administration and monitoring protocols. Furthermore, this work will enhance our knowledge of GABAA receptor pharmacology and provide a framework for future drug discovery pipelines.