Pharmacological Evaluation of Novel N‐ and C‐Modified Peptide Analogues of VV‐hemorphin‐5 and VV‐hemorphin‐7 as Potential Agents With Anti‐Seizure Activity

Recently, a series of N- and C-modified hemorphins have been synthesized, characterized and evaluated for their antibacterial potency. These analogues included amino acids such as cysteine (Cys), glutamic acid (Glu), and histidine (His), as well as 1-adamantanecarboxylic acid (Adam), and niacin (nicotinic acid) (Nic). The current study aimed to explore the anti-seizure potential of these compounds in mice. The role of opioid receptors (ORs) in their mechanism of action was evaluated both pharmacologically and through in silico methods. A battery of tests were used, including the 6-Hz and maximal electroshock seizures (MES) tests, as well as kainate (KA)-induced status epilepticus (SE), pentylenetetrazol (PTZ) and corneal kindling models. The intracerebroventricular infusion of peptide analogues, specifically those containing Cys, Glu, His and Adam but not Nic, showed reduced psychomotor seizures and seizure spread. The effective dosages were as follows: C-V (25 μg/5 μl-6 Hz and MES), H-V (6 and 12 μg/5 μl-6 Hz and MES), AC-V (12 μg/5 μl-MES) and AH-V (25 μg/5 μl-6 Hz). The efficacy of the compounds in preventing clonic seizures in PTZ-kindled mice was observed, except NCH7. Furthermore, C-V and AC-V were found to be effective in corneal-kindled mice and C-V against the KA-induced SE. Naloxone blocked the anti-seizure effect of C-V and AC-V, which was also confirmed by docking analysis. Our findings suggest that insertion of Cys and Glu (C-V and AC-V) and Cys, Adam, and Glu (AC-V) enhances the potential of these novel hemorphin analogues as effective anti-seizure agents.