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Toxins 2018, 10(1), 34; doi:10.3390/toxins10010034

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

1
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia
2
Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Pushchino 142290, Moscow Region, Russia
*
Author to whom correspondence should be addressed.
Received: 3 November 2017 / Revised: 31 December 2017 / Accepted: 2 January 2018 / Published: 7 January 2018
(This article belongs to the Special Issue Toxins in Drug Discovery and Pharmacology)
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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. View Full-Text
Keywords: nicotinic acetylcholine receptor; azemiopsin; preclinical studies; toxicity; pharmacokinetics; myorelaxant; Key Contribution; Investigation of the preclinical profile of azemiopsin demonstrated its high affinity and specificity for muscle type nicotinic acetylcholine receptor as well as good muscle relaxant capacity. Toxicology studies in mice indicated that azemiopsin was well tolerated during chronic dosing and showed no immunotoxicity, allergenic or mutagenic activity, which made it a good candidate for application as a local muscle relaxant. nicotinic acetylcholine receptor; azemiopsin; preclinical studies; toxicity; pharmacokinetics; myorelaxant; Key Contribution; Investigation of the preclinical profile of azemiopsin demonstrated its high affinity and specificity for muscle type nicotinic acetylcholine receptor as well as good muscle relaxant capacity. Toxicology studies in mice indicated that azemiopsin was well tolerated during chronic dosing and showed no immunotoxicity, allergenic or mutagenic activity, which made it a good candidate for application as a local muscle relaxant.
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MDPI and ACS Style

Shelukhina, I.V.; Zhmak, M.N.; Lobanov, A.V.; Ivanov, I.A.; Garifulina, A.I.; Kravchenko, I.N.; Rasskazova, E.A.; Salmova, M.A.; Tukhovskaya, E.A.; Rykov, V.A.; Slashcheva, G.A.; Egorova, N.S.; Muzyka, I.S.; Tsetlin, V.I.; Utkin, Y.N. Azemiopsin, a Selective Peptide Antagonist of Muscle Nicotinic Acetylcholine Receptor: Preclinical Evaluation as a Local Muscle Relaxant. Toxins 2018, 10, 34.

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