AUTHOR=Ojomoko Lucy O. , Kryukova Elena V. , Egorova Natalya S. , Salikhov Arthur I. , Epifanova Lyubov A. , Denisova Daria A. , Khomutov Alex R. , Sukhov Dmitry A. , Vassilevski Alexander A. , Khomutov Maxim A. , Tsetlin Victor I. , Shelukhina Irina V. 

TITLE=Inhibition of nicotinic acetylcholine receptors by oligoarginine peptides and polyamine-related compounds

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1327603

DOI=10.3389/fphar.2023.1327603

ISSN=1663-9812

ABSTRACT=<p>Oligoarginine peptides, known mostly for their cell-penetrating properties, are also inhibitors of the nicotinic acetylcholine receptors (nAChRs). Since octa-arginine (R8) inhibits α9α10 nAChR and suppresses neuropathic pain, we checked if other polycationic compounds containing amino and/or guanidino groups could be effective and tested the activity of the disulfide-fixed “cyclo”R8, a series of biogenic polyamines (putrescine, spermidine, and spermine), <italic>C</italic>-methylated spermine analogs, agmatine and its analogs, as well as acylpolyamine argiotoxin-636 from spider venom. Their inhibitory potency on muscle-type, α7 and α9α10 nAChRs was determined using radioligand analysis, electrophysiology, and calcium imaging. “Cyclo”R8 showed similar activity to that of R8 against α9α10 nAChR (IC<sub>50</sub> ≈ 60 nM). Biogenic polyamines as well as agmatine and its analogs displayed low activity on muscle-type <italic>Torpedo californica</italic>, as well as α7 and α9α10 nAChRs, which increased with chain length, the most active being spermine and its <italic>C</italic>-methylated derivatives having IC<sub>50</sub> of about 30 μM against muscle-type <italic>T. californica</italic> nAChR. Argiotoxin-636, which contains a polyamine backbone and terminal guanidino group, also weakly inhibited <italic>T. californica</italic> nAChR (IC<sub>50</sub> ≈ 15 μM), but it revealed high potency against rat α9α10 nAChR (IC<sub>50</sub> ≈ 200 nM). We conclude that oligoarginines and similar polycationic compounds effectively inhibiting α9α10 nAChR may serve as a basis for the development of analgesics to reduce neuropathic pain.</p>