# Basic and Translational Research on General Anesthetics

> **NIH NIH R35** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $685,731

## Abstract

Project Summary. General anesthesia, the reversible pharmacologic inhibition of neural functions underlying
consciousness, awareness, memory, and nociceptive motor responses, is an essential medical intervention.
There is a clear need for new anesthetic drugs with predictable kinetics and reduced toxicity, which will
facilitate medical procedural innovation, efficacy, efficiency, and accessibility. I have contributed to these goals
using two rigorous and complementary strategies. First, I have rigorously advanced basic science knowledge
of molecular anesthetic mechanisms in established targets such as GABAA receptors. This research has
revealed unexpectedly specific interactions between different general anesthetic chemotypes (etomidate
derivatives, methyl-phenyl allyl barbiturates or MPABs, neurosteroids like alphaxalone, and benzoyl alcohols)
and distinct sets of transmembrane inter-subunit sites in typical synaptic GABAA receptors. I also introduced
Monod-Wyman-Changeux (MWC) two-state co-agonist models for quantitative analysis of anesthetic effects in
these receptors. Second, recognizing that GABAA receptor-specific drugs have proven unsatisfactory as sole
clinical general anesthetic agents, I am among the first to adopt zebrafish as an unbiased pharmacodynamic
model to discover new hypnotic chemotypes that may act via multiple molecular targets, and to develop
transgenic lines to accelerate mechanisms research. The broad long-term objectives of this R35 (MIRA)
grant during the next five years and beyond are to further advance our understanding of anesthetic
mechanisms at the molecular level, to discover new chemical families with sedative-hypnotic activity,
and to create new transgenic zebrafish to test the roles of specific drug-receptor interactions in
anesthetic effects. Molecular knowledge areas that will be addressed by this project include, but are not
limited to improving the precision of anesthetic site mapping in GABAA receptors, developing MWC models that
account for differential agonist versus GABA modulation effects of the distinct site-selective anesthetic
chemotypes, probing the subunit arrangement and structures of other important (e.g. extra-synaptic) GABAA
receptor isotypes using subsite-specific anesthetics and mutations that selectively affect their actions, and
extending these structure-function approaches to other anesthetic-sensitive pentameric ligand-gated ion
channels. I will also apply the platform combining zebrafish larvae and real-time video analysis of up to 96
animals at a time to identify new sedative-hypnotic chemotypes in drug libraries and assess a variety of
sedative-hypnotic drug interactions. New hypnotic chemotypes will be characterized for effects in a panel of
molecular anesthetic targets using electrophysiology and pharmacologic tools. I will also develop new
transgenic zebrafish lines with knock-out or knock-in mutations in anesthetic target proteins as models for
testing if these targets mediate th...

## Key facts

- **NIH application ID:** 10831007
- **Project number:** 5R35GM141951-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** STUART A FORMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $685,731
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831007

## Citation

> US National Institutes of Health, RePORTER application 10831007, Basic and Translational Research on General Anesthetics (5R35GM141951-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10831007. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*