Carboxyl groups at the membrane interface as molecular targets for local anesthetics

Area of Science:

• Biochemistry
• Pharmacology
• Membrane Biophysics

Background:

• Tertiary amine drugs like chlorpromazine and dibucaine are used as local anesthetics.
• Understanding their interaction with cell membranes is crucial for anesthesia mechanisms.
• Carboxyl groups on membrane surfaces are potential binding sites for these drugs.

Purpose of the Study:

• To investigate the interaction between cationic tertiary amine drugs and carboxyl groups at membrane surfaces.
• To determine anesthetic binding affinities and their influence on membrane ionization.
• To propose potential binding sites for local anesthetics in ion channels and ATPases.

Main Methods:

• Utilized spin-labeled stearic acid in egg lecithin liposomes to provide and monitor carboxyl groups.
• Spectrophotometric determination of membrane anesthetic concentrations.
• Performed pH titrations of anesthetic-treated, spin-labeled membranes.

Main Results:

• Membrane anesthetic concentrations, not aqueous ones, dictate drug influence on surface carboxyl groups.
• Intramembrane association constants for chlorpromazine and dibucaine with fatty acids were both 10(2) M-1.
• Observed pK shifts in fatty acids were greater than predicted by uniform distribution, indicating higher affinity for superficial carboxyl groups.

Conclusions:

• Local anesthetics exhibit increased affinity for superficial carboxyl groups on cell membranes.
• This enhanced affinity may underlie the resting block of voltage-gated sodium channels.
• Proposed binding sites for local anesthetics include voltage-gated Na+ channels and sarcoplasmic reticulum Ca(2+)-ATPase.