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

• DOI: 10.3389/fphar.2023.1327603
• Publication Date: 2023-12-15T11:05:48Z
• Authors: Lucy O. Ojomoko; Elena V. Kryukova; Natalya S. Egorova; Arthur I. Salikhov; Lyubov A. Epifanova; Daria A. Denisova; Alex R. Khomutov; Dmitry A. Sukhov; Alexander A. Vass...; Maxim A. Khomutov; Victor I. Tsetlin; Irina V. Shelukhina
• Keywords: Pharmacology; 0301 basic medicine; 03 medical and health sciences; polyamines; acylpolyamine; radioligand analysis; Therapeutics. Pharmacology; RM1-950; nicotinic acetylcholine receptor; oligoarginine; electrophysiology

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), C-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 (IC50 ≈ 60 nM). Biogenic polyamines as well as agmatine and its analogs displayed low activity on muscle-type Torpedo californica, as well as α7 and α9α10 nAChRs, which increased with chain length, the most active being spermine and its C-methylated derivatives having IC50 of about 30 μM against muscle-type T. californica nAChR. Argiotoxin-636, which contains a polyamine backbone and terminal guanidino group, also weakly inhibited T. californica nAChR (IC50 ≈ 15 μM), but it revealed high potency against rat α9α10 nAChR (IC50 ≈ 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.