Anticonvulsant evaluation and docking analysis of VV‐Hemorphin‐5 analogues

Abstract

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-NH 2 and Val-Val-Tyr-Pro-Trp-Thr-Aa1-NH 2 ) 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. K E Y W O R D Santiconvulsant activity, docking, Hemorphin analogues, mice, SPPS

Hemorphins—From Discovery to Functions and Pharmacology

“…Importantly, not only the position, but also the nature of the incorporated group had an impact on this phenomenon. The obtained data provide the basis for anticipation that the described compounds may be considered as a promising template for future design of the more active analogues, as well as in studies of other models of epilepsy [52,[89][90][91][92][93].…”

“…It is noteworthy that, when isoleucine or 2-aminoisobutyric acid was added at position 1, a decrease in biological activity has been observed. Incorporation of Orn (2,5-diaminopentanoic acid) at Gln position of VV-hemorphin-5 and Dab (2,5-diaminobutanoic acid) moiety at Gln position of VV-hemorphin-7 peptide, respectively led to the analogues posessing good efficacy against the three seizure models [52,[89][90][91][92].…”

Synthesis and characterization of new 5,5′-dimethyl- and 5,5′-diphenylhydantoin-conjugated hemorphin derivatives designed as potential anticonvulsant agents

“…(5 mL per ventricle) at doses of 0.25, 0.5 and 1 mg, respectively, by means of 28-gauge stainless steel needles attached to 10 mL Hamilton s syringes as described in previous studies. 49,50 The antiseizure effect was evaluated 10 min following the treatment. The doses were chosen based on our previous studies.…”

“…39 Based on our previous studies, we showed that hemorphins and their analogues, containing non-proteinogenic and/or natural amino acids, from the N-or C-terminus of the molecules demonstrated dose-and phase-dependent anticonvulsant activity and a lack of neurotoxicity in the rotarod test. [47][48][49][50][51] Our group is one of the leading pioneers in the exploration of anticonvulsant activity of these perspective biopeptides. [47][48][49][50][51] As a natural extension of our research in the synthesis and characterization of new hemorphin analogues as potential anticonvulsants and because of all the above mentioned, herein we illustrated the potential of new N-modified hybrid analogue hemorphins containing a C-5 substituted hydantoin residue as anticonvulsants and inhibitors of sodium channels.…”

“…[47][48][49][50][51] Our group is one of the leading pioneers in the exploration of anticonvulsant activity of these perspective biopeptides. [47][48][49][50][51] As a natural extension of our research in the synthesis and characterization of new hemorphin analogues as potential anticonvulsants and because of all the above mentioned, herein we illustrated the potential of new N-modified hybrid analogue hemorphins containing a C-5 substituted hydantoin residue as anticonvulsants and inhibitors of sodium channels. We aimed to synthesize new potent anticonvulsant N-modified hybrid analogues of hemorphins containing a C-5 substituted hydantoin, with proven pharmacological activity, to the peptide fragment.…”