The objective of this project are to define how compounds of anesthetic interest interact with lipid membranes and to correlate the concentration of these compounds at the water-membranes interface with structurally similar compounds, each ranging from potent anesthetics to non anesthetics, will be determined to test the hypothesis that an anesthetic effect occurs only when the concentration of anesthetic at the interface is sufficient. This hypothesis is motivated by recent findings by Eger that lipophilicity alone is not sufficient to predict the potency of inhaled anesthetics. A minimum level of hydrophilicity is also required to produce anesthesia. In the first stage of the proposed calculations, the potential energy functions needed in molecular dynamics calculations, will be designed and tested by comparing calculated solubilities of the selected compounds in water and hexane with the measured solubilities. Then, the transfer of these compounds across interfaces of increasing complexity (water-hexane, water-glycolipid, water-phospholipid) will be simulated. The binding of anesthetics to the interface will be analyzed in terms of perturbations in the structure of membranes and interfacial water created by these compounds. An understanding of the molecular basis for interactions of anesthetic vs. non anesthetic compounds with the water-membrane interface will advance our knowledge of the site and mechanism of anesthetic action. Improved correlation between anesthetic and physical-chemical properties of anesthetic compounds that should result from the proposed calculations will be helpful in future effects to design better anesthetics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
1P01GM047818-04S1
Application #
2781124
Study Section
Project Start
Project End
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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