Abstract
Azemiopsin (Az), a linear peptide from the Azemiops feae viper venom, contains no disulfide bonds, is a high-affinity and selective inhibitor of nicotinic acetylcholine receptor (nAChR) of muscle type and may be considered as potentially applicable nondepolarizing muscle relaxant. In this study, we investigated its preclinical profile in regard to in vitro and in vivo efficacy, acute and chronic toxicity, pharmacokinetics, allergenic capacity, immunotoxicity and mutagenic potency. The peptide effectively inhibited (IC50 ~ 19 nM) calcium response of muscle nAChR evoked by 30 μM (EC100) acetylcholine but was less potent (IC50 ~ 3 μM) at α7 nAChR activated by 10 μM (EC50) acetylcholine and had a low affinity to α4β2 and α3-containing nAChR, as well as to GABAA or 5HT3 receptors. Its muscle relaxant effect was demonstrated at intramuscular injection to mice at doses of 30–300 µg/kg, 30 µg/kg being the initial effective dose and 90 µg/kg—the average effective dose. The maximal muscle relaxant effect of Az was achieved in 10 min after the administration and elimination half-life of Az in mice was calculated as 20–40 min. The longest period of Az action observed at a dose of 300 µg/kg was 55 min. The highest acute toxicity (LD50 510 μg/kg) was observed at intravenous injection of Az, at intramuscular or intraperitoneal administration it was less toxic. The peptide showed practically no immunotoxic, allergenic or mutagenic capacity. Overall, the results demonstrate that Az has good drug-like properties for the application as local muscle relaxant and in its parameters, is not inferior to the relaxants currently used. However, some Az modification might be effective to extend its narrow therapeutic window, a typical characteristic and a weak point of all nondepolarizing myorelaxants.
Highlights
A linear peptide azemiopsin (Az) isolated from the Azemiops feae viper venom contains no disulfide bonds [1] and can be prepared by peptide synthesis
Earlier we have shown that histidine residue is essential for Az activity [1]; its replacement by alanine resulted in strong decrease in capacity to bind to Torpedo nicotinic acetylcholine receptor
We investigated the preclinical profile of Az in regard to in vitro and in vivo efficacy, acute and chronic toxicity, pharmacokinetics, allergenic capacity, immunotoxicity and mutagenic potency
Summary
A linear peptide azemiopsin (Az) isolated from the Azemiops feae viper venom contains no disulfide bonds [1] and can be prepared by peptide synthesis It is a high-affinity and selective inhibitor of muscle-type nicotinic acetylcholine receptor (nAChR) involved in fast synaptic signal transduction at nerve-muscle junction [2]. Muscle relaxants reduce the tone of the skeletal muscle with a decrease in motor activity up to complete immobilization. These drugs are generally classified into central muscle relaxants, which disrupt the transmission of excitation in the central nervous system and muscle relaxants of peripheral action that primarily and disturb neuromuscular transmission. NMRs (such as d-tubocurarine, atracurium, rocuronium) block the binding of acetylcholine to nAChR and disturb its function [4]
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