Synthesis, Characterization and Biological Investigation of New N-Modified Spinorphin Analogs

Abstract

The emergence of diverse peptide derivatives has been due to constant efforts to find a specific peptide with pronounced biological activity for effective application as a therapeutic. Spinorphin-peptide products have been reported to possess various applications and properties. In the present study, spinorphin peptides with a rhodamine residue and a modification in the amino acid backbone were synthesized by a solid-phase method using Fmoc chemistry. The results obtained from the spectral and electrochemical techniques used: Scanning electron microscopy (SEM), UV-vis, fluorescence, infrared spectroscopy (IR), and voltammetry were used to elucidate the structural characteristics and some physicochemical properties to gain insight into their behavior in the solid state and in aqueous solutions with different pHs. Both Rh-S5 and Rh-S6 had compound anticonvulsant effect comparable to Rh-S against psychomotor seizures at the highest dose of 20 μg. Furthermore, Rh-S6 showed a strong ability to inhibit seizure propagation and had a similar threshold to Rh-S against the intravenous pentylenetetrazol induced clonic seizure in mice; one of the three hybrid spinorphin analogs tested when screened for anticonvulsant activity. Biological tests against several bacterial pathogens such as Staphylococcus aureus, Escherichia coli, and Bacillus cereus showed similar results to negative control of the new peptide derivatives. The compounds also showed weak activity against Candida albicans fungus. The antioxidant testing results revealed more than 50% activity by reviewing the radical deterrence capabilities of 2,2-diphenyl-1-picrylhydrazyl (DPPH). The results are indicative of the ongoing search for universal antimicrobial agents with pronounced synergism when used simultaneously as anticonvulsant, antibacterial, and antifungal agents.

Synthesis, characterization and evaluation of anti‐hyperalgesia, anticonvulsant and antioxidant activity of novel VV‐hemorphin‐5 analogs

“…Along with determining the acid–base constants, calculating the partition coefficient (logP) is an essential parameter for explaining the in vivo functions of the biologically active molecules. [ 6 ] The “shake‐flask method” of analyte was placed in two immiscible phases: n ‐octanol and phosphate buffer solution with pH 7.4 and subsequent chromatographic (HPLC) detection using a calibration method of standard additives to determine the coefficients of the analytical function was used to assess logP of the studied compounds. The parameters for recording the analytical signals are described in Section 4.…”

“…Previous research has shown that valorphine compounds have analgesic action by inhibiting pain receptors. [ 6 ] Furthermore, valorphine molecules have been displayed in mice to attenuate convulsive processes. [ 6 ] The possibility of the molecule passing through cell membranes or other subcellular structures is the basis for all the listed biological activities of the compounds, for which the structure and some physicochemical characteristics such as redox behavior, solubility, pH behavior, and AOA are important.…”

“…For the first time, the idea of introducing unnatural, nonproteinogenic, and some natural amino acids for the synthesis of new modified analogs of hemorphins was successfully implemented by Todorov et al [6,13] Due to the interesting properties shown by some of the recently obtained hemorphin analogs, herein the main goal of getting new peptides following the structures: Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH 2 and Adam-Val-Val-Tyr-Xxx-Trp-Thr-Gln-NH 2 , where Xxx is Ac5c (1aminocyclopentane-1-carboxylic acid), Ac6c (1-aminocyclohexane-1carboxylic acid), Ac7c (1-aminocycloheptane-1-carboxylic acid), and Adam is the low-molecular-weight lipophilic adamantyl building block (see Figure 1). The synthesis of this kind of peptide molecules that contain conformationally constrained amino acids such as cycloalkane building blocks and adamantane groups is a strategy to improve the propensity for aqueous solubility and/or to increase their affinity for the target receptor or enzyme.…”

“…[1,2] These peptides, atypical opioids with antinociceptive effects, have been identified in various biological fluids and tissues, including the peripheral and central nervous systems (CNSs). [3][4][5][6] Hemorphin-4 (Tyr-Pro-Trp-Thr) and hemorphin-5 (Val-Val-Tyr-Pro-Trp-Thr-Gln) were established to induce potent antinociceptive effects on two models of phasic and tonic nociception due to activation of the brain mu-opioid receptors. [7] We have recently shown that VV-hemorphin-5 (valorphin) has a significant antinociceptive effect after intracerebroventricular injection suppressing phasic and tonic nociception.…”

“…Recently, we reported that newly synthesized hemorphin‐5 peptide analogs had anticonvulsant and anti‐hyperalgesia activity in different tests and methods. [ 6,9,13 ] In the present study, the novel hemorphin derivatives were synthesized by incorporating unnatural, conformationally constrained amino acids into the peptide chain to continue searching the structure–biological activity relationship. They were characterized and explored in vivo for potential neurotoxicity, anticonvulsants, and antinociceptive activity in mice.…”