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Structure-activity relationship of lidocaine homologs producing tonic and frequency-dependent impulse blockade in nerve.

Published Article
The Journal of pharmacology and experimental therapeutics
Publication Date
PMID: 2423682


Experiments were done to assess the relationship of the chemical properties of local anesthetics to their ability to block neuronal impulse conduction, using a series of hitherto unavailable homologs of lidocaine. These molecules varied in the number and arrangement of alkyl groups attached to the tertiary amine nitrogen. Each compound was applied to desheathed sciatic nerves of frogs (Rana pipiens) mounted in a sucrose gap recording chamber. Compound action potentials (AP) were recorded at room temperature (20-23 degrees C) and the potency of each anesthetic determined from the concentration required to produce a 40% reduction in the amplitude of the AP at low-frequency stimulation: 1 min-1. This reduction was called Bt. An additional Bt was measured from the further decrease in amplitude of the AP during high-frequency stimulation (10 and 40 Hz). Tonic and phasic blocking potencies were analyzed as functions of the calculated drug partition coefficients, and the known molecular weights, molecular configurations and pKa values. Potency for Bt increased with increasing length of n-alkyl groups attached to the terminal amine, whereas it decreased as the length of the alkyl group connecting the amide bond to the terminal amine was increased. However, when considered in terms of their physicochemical properties, the homologs showed a potency for Bt that increased uniformly with increasing partition coefficient. This analysis revealed a strong positive correlation between tonic potency and partitioning into octanol for both neutral and protonated anesthetic species but little correlation with molecular weight or pKa. However, Bt did not depend uniquely on hydrophobicity, as predicted if lipophilic partitioning alone determined potency.(ABSTRACT TRUNCATED AT 250 WORDS)

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