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.