Role of the Guanidinium Groups in Ligand–Receptor Binding of Arginine-Containing Short Peptides to the Slow Sodium Channel: Quantitative Approach to Drug Design of Peptide Analgesics

Several arginine-containing short peptides have been shown by the patch-clamp method to effectively modulate the Na(V)1.8 channel activation gating system, which makes them promising candidates for the role of a novel analgesic medicinal substance. As demonstrated by the organotypic tissue culture method, all active and inactive peptides studied do not trigger the downstream signaling cascades controlling neurite outgrowth and should not be expected to evoke adverse side effects on the tissue level upon their medicinal administration. The conformational analysis of Ac-RAR-NH(2), Ac-RER-NH(2), Ac-RAAR-NH(2), Ac-REAR-NH(2), Ac-RERR-NH(2), Ac-REAAR-NH(2), Ac-PRERRA-NH(2), and Ac-PRARRA-NH(2) has made it possible to find the structural parameter, the value of which is correlated with the target physiological effect of arginine-containing short peptides. The distances between the positively charged guanidinium groups of the arginine side chains involved in intermolecular ligand–receptor ion–ion bonds between the attacking peptide molecules and the Na(V)1.8 channel molecule should fall within a certain range, the lower threshold of which is estimated to be around 9 Å. The distance values have been calculated to be below 9 Å in the inactive peptide molecules, except for Ac-RER-NH(2), and in the range of 9–12 Å in the active peptide molecules.