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 nonspecifically modulate a variety of receptors, leading to myriad adverse side effects. By decreasing the number of receptors affected while maintaining those required to produce general anesthesia, the side effect profiles may be significantly diminished, and the overall safety and efficacy of inhaled anesthetics 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 GABAA 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 GABAA 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.
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.
Expanesthetics has applied this discovery to create a platform for discovering 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, two agents appeared 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.
To read more about this discovery, the following publications are currently available:
Start Here (best summary of Robert's hypothesis):
Brosnan RJ, Pham TL. 2018. Anesthetic-sensitive ion channel modulation is associated with a molar water solubility cut-off. BMC Pharmacol Toxicol. 19:57. https://www.ncbi.nlm.nih.gov/pubmed/30217234
Brosnan RJ, Ramos K, Aguiar AJA, Cenani A, Knych HK. 2022. Anesthetic Pharmacology of the Mint Extracts L-Carvone and Methyl Salicylate. Pharmacology. 107(3-4):167-178. https://pubmed.ncbi.nlm.nih.gov/35100605/
Cenani A, Brosnan RJ, Knych HK. 2019. In vitro and in vivo GABAA Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid. Pharmacology. 103(1-2):10-16. https://pubmed.ncbi.nlm.nih.gov/30332672/
Brosnan RJ. 2018. Cardiovascular Effects of A Novel Inhaled Anesthetic in Dogs. Lecture presented at the annual meeting of the American Society of Anesthesiologists, San Francisco, CA. https://expanesthetics.com/brosnanlecture2018
Brosnan RJ, Fukushima FB, Pham TL. 2017. Anesthetic synergy between two n-alkanes. Vet Anaesth Analg. 44(3):577-588. https://www.ncbi.nlm.nih.gov/pubmed/28583773
Brosnan RJ, Pham TL. 2016. GABAA Receptor Modulation by Phenyl Ring Compounds is Associated with a Molar Water Solubility Cut-Off Value. Pharmacology. 98(1-2):13-9. https://www.ncbi.nlm.nih.gov/pubmed/26986632
Brosnan RJ, Pham TL. 2014. Hydrocarbon molar water solubility predicts NMDA vs. GABAA receptor modulation. BMC Pharmacol Toxicol. 15:62. https://www.ncbi.nlm.nih.gov/pubmed/25410726
1. National Institutes of Health National Institutes of General Medical Sciences Grant GM092821-02.