STRUCTURE-ACTIVITY RELATIONS FOR FREQUENCY-DEPENDENT SODIUM-CHANNEL BLOCK IN NERVE BY LOCAL-ANESTHETICS

Abstract

Different local anesthetic drug structures differ significantly in their capabilities for producing frequency (f)-dependent Na channel block. Voltage-clamped frog [Rana catesbeiana] myelinated nerve preparations were utilized to investigate structure-activity relations for several local anesthetic drugs [tocainide, W36017, prilocaine, procaine, GEA 968, mepivicaine, lidocaine, bupivicaine, etidocaine, tetracaine, alprenolol, d-propranolol], including the kinetics of f-dependent excitability block. Lipid solubility was an important determinant of closed channel blocking potency, at least within the amide-linked series of local anesthetics. The ether-linked (.beta. blockers) and ester-linked local anesthetics appear to be relatively more potent at closed channel block than drugs of the amide-linked series. F-dependent block increments are greater for drugs of lower lipid solubility, supporting the modulated drug receptor hypothesis that intracellular drug forms participate in the open channel binding involved in f-dependent blocking. Molecular size has been shown to be a very important determinant of closed channel block escape rates with smaller drug structures showing faster escape rates from f-dependent increments in channel block.