Synthesis, conformational and pharmacological studies of glycosylated chimeric peptides of Met-enkephalin and FMRFa

Abstract

Our previous study showed that a chimeric peptide of Met-enkephalin and FMRFamide, YFa (YGGFMKKKFMRFa) not only caused antinociception and potentiated morphine analgesia but also blocked the development of tolerance and physical dependence. In the continuation of that study three chimeric analogues of YFa, [Ser⁵]YFa, [O-Glu-Ser⁵]YFa and [O-Gal-Ser⁵]YFa, were synthesized. To increase the bioavailability and penetration of blood brain barrier (BBB), glycosylated analogues, [O-Glu-Ser⁵]YFa and [O-Gal-Ser⁵]YFa, have been synthesized by solid phase peptide synthesis by building block method using anomeric acetate activation method. Circular dichroism studies showed that all the three chimeric peptides are stable and have a propensity for adopting helical conformation in the presence of membrane mimicking solvent. In comparison of parent chimeric peptide YFa, helicity of [Ser⁵]YFa, [O-Glu-Ser⁵]YFa and [O-Gal-Ser⁵]YFa has decreased. Pharmacological studies using tail-flick latency in mice showed that [O-Glu-Ser⁵]YFa have increased analgesia and bioavailability in comparison of [O-Gal-Ser⁵]YFa and non-glycosylated analogue [Ser⁵]YFa. Exhibition of enhanced analgesia by [O-Glu-Ser⁵]YFa as compared to [O-Gal-Ser⁵]YFa seems to be due to preference of GLUT-1 transporter system for glucose.