Introduction of lipidization-cationization motifs affords systemically bioavailable neuropeptide Y and neurotensin analogs with anticonvulsant activities

Journal of Peptide Science : an Official Publication of the European Peptide Society
Brad R GreenGrzegorz Bulaj

Abstract

The neuropeptides galanin (GAL), neuropeptide Y (NPY) or neurotensin (NT) exhibit anticonvulsant activities mediated by their respective receptors in the brain. To transform these peptides into potential neurotherapeutics, their systemic bioavailability and metabolic stability must be improved. Our recent studies with GAL analogs suggested that an introduction of lipoamino acids in the context of oligo-Lys residues (lipidization-cationization motif) significantly increases their penetration into the brain, yielding potent antiepileptic compounds. Here, we describe an extension of this strategy to NPY and NT. Rationally designed analogs of NPY and NT containing the lipidization-cationization motif were chemically synthesized and their physicochemical and pharmacological properties were characterized. The analogs NPY-BBB2 and NT-BBB1 exhibited increased serum stability, possessed log D > 1.1, retained high affinities toward their native receptors and produced potent antiseizure activities in animal models of epilepsy following intraperitoneal administration. Our results suggest that the combination of lipidization and cationization may be an effective strategy for improving systemic bioavailability and metabolic stability of vari...Continue Reading

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Citations

Mar 16, 2012·Epilepsia·Jeanelle PortelliIlse Smolders
Apr 8, 2014·Molecular Neurobiology·Elke ClynenJean-Michel Rigo
Apr 7, 2017·Neurochemical Research·Cameron S MetcalfGrzegorz Bulaj
Feb 23, 2011·Natural Product Reports·Charles R RobertsonGrzegorz Bulaj

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