Key Takeaway
Expanesthetics has discovered 3 new anesthetic drug candidates that suggest our platform may help mitigate intraoperative hypotension.
Cardiovascular Stability at MAC
In preclinical studies, Expanesthetics has identified three novel volatile anesthetic candidates that maintained substantially greater mean arterial pressure at MAC concentrations than conventional inhaled anesthetics. Some of this work has been published [1], and further publications are in development.
Compared with sevoflurane, isoflurane, and halothane, all three of our experimental compounds demonstrated mean arterial pressures at or near normotensive levels at MAC in rat studies. Dose-dependent cardiovascular depression has been an accepted side-effect of every available volatile agent, but if these results are replicable in humans it would represent a clinically meaningful improvement.
A Novel Mechanism of Action
Conventional volatile anesthetics modulate both GABAA and NMDA receptors, as well as many other receptors and ion channels [4]. Across a broad concentration range, including and exceeding predicted MAC levels, all three of these compounds demonstrated negligible NMDA receptor modulation.
This suggests a fundamentally different receptor profile, one that may open the door to anesthetic candidates with meaningfully fewer unwanted side-effects.
This is in sharp contrast to the conventional volatile anesthetics, which show 25–45% NMDA inhibition at MAC concentrations, with progressively greater inhibition at higher concentrations [2,3]. This suggests a fundamentally different receptor profile, one that may open the door to anesthetic candidates with meaningfully fewer unwanted side-effects.
Built on a Groundbreaking Discovery
Expanesthetics' discovery platform grew out of research led by Dr. Robert Brosnan at UC Davis, supported by an NIH R01 grant, exploring a relationship between the physical properties of small molecules and their receptor-level behavior. Dr. Brosnan's work demonstrated that a compound's molar water solubility could help predict which neuroreceptors it could modulate and, critically, which ones it would not [5,6].
In the case of these three candidates, we succeeded in achieving a more targeted receptor profile. The lack of NMDA modulation was predicted based on each compound's molar water solubility and confirmed through direct studies. The fact that these compounds also preserve blood pressure further suggests that our discovery platform can identify candidates with distinct and potentially meaningful clinical advantages.
That insight made it possible to strategically screen for anesthetic candidates with more targeted receptor profiles rather than relying on the brute force strategies that characterized earlier eras of anesthetic discovery. The platform identifies molecules predicted to have a specific receptor profile, allowing us to employ a more focused approach as we synthesize compounds and test them for anesthetic activity.
What Else This Could Mean
While these three normotensive candidates represent important and consistent output from our platform, they are not the only evidence that it can identify compounds with distinct clinical profiles.
The platform has also identified:
- candidates with rapid kinetics approaching those of xenon (including 2 of the 3 compounds discussed above)
- a sublimating solid capable of producing anesthesia
- compounds with analgesic properties
- a candidate that demonstrates synergy with propofol, a distinct characteristic from currently available inhaled anesthetics
Example: A new non-ether inhaled anesthetic
A recent candidate Expanesthetics studied was the first non-ether inhaled anesthetic to reach its stage of development in more than 60 years. In preclinical models, it demonstrated the ability to blunt increases in heart rate and blood pressure in response to noxious stimuli at and below MAC, a property not seen with conventional volatile agents. The fact that the platform identified a promising candidate in an entirely different chemical class suggests its reach extends beyond traditional ether-based anesthetics.
Each represents a different axis of improvement, and together they suggest a discovery engine with broad potential.
Expanesthetics was built to expand what is possible in inhaled anesthesia. The preclinical evidence suggests that expansion is already underway.
References
- Brosnan RJ, Austin S, Antognini JF. A New General Anesthetic BTTE: Physical Properties, Hypnotic and Hemodynamic Effects in Rats, and Effects on GABA and NMDA Receptors Expressed in Frog Oocytes. Anesth Analg. 2026 Feb 3. Epub ahead of print. (View Reference)
- Hollmann MW, Liu HT, Hoenemann CW, Liu WH, Durieux ME. Modulation of NMDA receptor function by ketamine and magnesium. Part II: interactions with volatile anesthetics. Anesth Analg. 2001 May;92(5):1182-91. (View Reference)
- Ogata J, Shiraishi M, Namba T, Smothers CT, Woodward JJ, Harris RA. Effects of anesthetics on mutant N-methyl-D-aspartate receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther. 2006 Jul;318(1):434-43. (View Reference)
- Kale KM, Goldstein PA, Pandit JJ. Are "GABAergic" Agents Really So Selective for GABA? Implications for Single- versus Multi-Site Hypotheses From Promiscuous Behavior of Anesthetics and Their Molecular Targets In Vitro. Anesth Analg. 2026 Jan 23. Epub ahead of print. (View Reference)
- Brosnan RJ, Pham TL. Hydrocarbon molar water solubility predicts NMDA vs. GABAA receptor modulation. BMC Pharmacol Toxicol. 2014 Nov 19;15:62. (View Reference)
- Brosnan RJ, Pham TL. Anesthetic-sensitive ion channel modulation is associated with a molar water solubility cut-off. BMC Pharmacol Toxicol. 2018 Sep 14;19(1):57. (View Reference)