Inside Our Discovery Engine

A Groundbreaking Discovery

UC Davis Professor Robert Brosnan, DVM, PhD studied under Dr. Ted Eger (one of the historic leaders in anesthetic research) at UCSF. Dr. Brosnan developed his hypothesis about how volatile general anesthetic compounds work through a million-dollar NIH R01 grant¹, later supported through a study funded by a competitive University of California proof of concept grant.

Current inhaled anesthetics affect a wide variety of receptors in the nervous system, leading to myriad adverse side effects. By decreasing the number of receptors affected while maintaining those required to produce general anesthesia, it is possible that the side-effect profiles may be significantly diminished and the overall quality of inhaled anesthesia may be significantly improved. Dr. Brosnan's discovery has made it possible to screen molecules for their ability to modulate these receptors, which provides the opportunity for new inhaled anesthetics with novel mechanisms of action.

For example, while all current volatile anesthetics modulate both GABA_A and NMDA receptors, we have identified a wide variety of novel volatile general anesthetics that were successfully predicted to avoid NMDA modulation while maintaining effects at GABA_A receptors. By modulating fewer receptors, we predict that these agents will have fewer side effects, and preliminary findings in animals support such a hypothesis. In addition, we are able to screen for new inhaled anesthetics outside of the traditional ethers and alkanes. This creates the possibility of finding agents in new chemical classes with new beneficial effects associated with their novel structures.

The Key Role of Molar Water Solubility

While the current inhaled general anesthetics came to market largely due to improvements in pharmacokinetics, Dr. Brosnan's discovery creates an opportunity for disruption in the market because it allows for the development of new inhaled general anesthetics with improvements in pharmacodynamics as well. This video outlines how Expanesthetics is applying this science to its development work.

Promising Results

Expanesthetics has applied this discovery to create a platform for identifying new inhaled general anesthetics. The company has already generated a variety of drug candidates that have shown promising results. Some have shown potential for superior side-effect profiles. For example, three agents appear to be normotensive at concentrations at and around MAC. Other candidates may have the potential for beneficial new effects, such as analgesia. The most recent candidate the company studied was the first non-ether inhaled general anesthetic to arrive at its stage of development in more than 60 years, and demonstrated the ability to blunt increases in heart rate and blood pressure in response to noxious stimuli at and below MAC.