Anticonvulsant evaluation and docking analysis of VV-Hemorphin-5 analogues.
VV-Hemorphin-5 is an endogenous opioid peptide of the Hemorphin family with affinity at opioid receptors. A series of C-amide analogues have been synthesized, based on the structure of VV-Hemorphin-5, modified at position 1 and 7 by the un/natural amino acids (Aa8-Val-Val-Tyr-Pro-Trp-Thr-Gln-NH2 and Val-Val-Tyr-Pro-Trp-Thr-Aa1-NH2 ) using SPPS, Fmoc-chemistry. The peptide derivatives were evaluated for their anticonvulsant activity in three acute seizure tests in male ICR mice, the maximal electroshock (MES), the 6 Hz psychomotor seizure test, and the timed intravenous pentylenetetrazole (ivPTZ) infusion test. Their neurotoxicity was assessed in the rotarod test. Among the tested peptide analogues, V4 showed anticonvulsant activity in the three seizure tests that was comparable to the VV-Hemorphin-5 (V1) used as a positive control. While V5, V6, and V7 peptide derivatives exhibited anticonvulsant activity in the MES and 6 Hz test, they were inactive (V7) or showed pro-convulsant effect (V5 and V6) in the i.v. PTZ test. At a dose of 10 μg/mouse the peptide V2 was effective against clonic seizures induced by PTZ. Motor coordination was not affected by newly developed analogues of VV-Hemorphin-5. Docking study results suggest that kappa opioid receptor binding could be the mechanism of action of peptide derivatives with anticonvulsant activity. The results suggest that incorporation of nonproteinogenic and/or natural amino acids at position 1 and 7 of the VV-Hemorphin-5 scaffold deserve further evaluation in models of epilepsy and derivatization.
['Todorov|Petar|P|', 'Rangelov|Miroslav|M|', 'Peneva|Petia|P|', 'Todorova|Nadezhda|N|', 'Tchekalarova|Jana|J|0000-0003-1640-5099']
D000595:Amino Acid Sequence D000818:Animals D000927:Anticonvulsants D004597:Electroshock D006454:Hemoglobins D008297:Male D008813:Mice, Inbred ICR D062105:Molecular Docking Simulation D015394:Molecular Structure D018847:Opioid Peptides D010433:Pentylenetetrazole D010446:Peptide Fragments D011485:Protein Binding D011597:Psychomotor Performance D017465:Receptors, Opioid, delta D017473:Receptors, Opioid, kappa D012640:Seizures D013329:Structure-Activity Relationship
docking SPPS anticonvulsant activity mice Hemorphin analogues