Chemical Conjugation of the Neuropeptide Kyotorphin and Ibuprofen Enhances Brain Targeting and Analgesia

• Type: Article in International Scientific Journal
• Date: 2011

Authors

Ribeiro, MMB (Author) Other; Pinto, ART (Author) Other; Domingues, MM (Author) Other; Serrano, I (Author) Other; Heras, M (Author) Other; Bardaji, ER (Author) Other; Isaura Tavares (Author) FMUP; Castanho, MA (Author) Other

Journal

Title: Molecular Pharmaceutics

Vol. 8

Pages: 1929-1940

ISSN: 1543-8384

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 33 Citations

Scopus - 33 Citations

Other information

Authenticus ID: P-002-MZG

DOI: 10.1021/mp2003016

Abstract (EN): The pharmaceutical potential of natural analgesic, peptides is mainly hampered by their inability to cross the blood-brain barrier, BBB. Increasing peptide-cell membrane Ibuprofen affinity through drug design is a promising strategy to overcome this limitation. To address this challenge, we grafted ibuprofen (IBP), a nonsteroidal anti-inflammatory drug, to kyotorphin (L-Tyr-L-Arg, KTP), an analgesic neuropeptide unable to cross BBB. Two new KTP derivatives, IBP-KTP (IbKTP-OH) and IBP-KTP-amide (IbKTP-NH(2)), were synthesized and characterized for membrane interaction, analgesic activity and mechanism of action. Ibuprofen enhanced peptide-membrane interaction, endowing a specificity for anionic fluid bilayers. A direct correlation between anionic lipid affinity and analgesic effect was established, IbKTP-NH(2) being the most potent analgesic (from 25 mu mol.kg(-1)). In vitro, IbKTP-NH(2) caused the biggest shift in the membrane surface charge of BBB endothelial cells, as quantified using zeta-potential dynamic light scattering. Our results suggest that IbKTP-NH(2) crosses the BBB and acts by activating both opioid dependent and independent pathways.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12