Azemiopsin, a Selective Peptide Antagonist of Muscle Nicotinic Acetylcholine Receptor: Preclinical Evaluation as a Local Muscle Relaxant.

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 similar to 19 nM) calcium response of muscle nAChR evoked by 30 M (EC100) acetylcholine but was less potent (IC50 similar to 3 M) at 7 nAChR activated by 10 M (EC50) acetylcholine and had a low affinity to 42 and 3-containing nAChR, as well as to GABA(A) or 5HT(3) receptors. Its muscle relaxant effect was demonstrated at intramuscular injection to mice at doses of 30-300 mu g/kg, 30 mu g/kg being the initial effective dose and 90 mu g/kgthe 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 mu g/kg was 55 min. The highest acute toxicity (LD50 510 g/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.