Endothelium-Mediated Action of Analogues of the Endogenous Neuropeptide Kyotorphin (Tyrosil-Arginine): Mechanistic Insights from Permeation and Effects on Microcirculation
ACS Chem. Neurosci
; 7(8): p. 1130-1140, 2016.
Article
| SES-SP, SESSP-IBPROD, SES-SP
| ID: but-ib14534
Biblioteca responsable:
BR78.1
Ubicación: BR78.1
ABSTRACT
Kyotorphin (KTP) is an endogenous peptide with analgesic properties when administered into the central nervous system (CNS). Its amidated form (L-Tyr-L-Arg-NH2; KTP-NH2) has improved analgesic efficacy after systemic administration, suggesting blood-brain barrier (BBB) crossing. KTP-NH2 also has anti-inflammatory action impacting on microcirculation. In this work, selected derivatives of KTP-NH2 were synthesized to improve lipophilicity and resistance to enzymatic degradation while introducing only minor changes in the chemical structure N-terminal methylation and/or use of D amino acid residues. Intravital microscopy data show that KTP-NH2 having a D-Tyr residue, KTP-NH2-DL, efficiently decreases the number of leukocyte rolling in a murine model of inflammation induced by bacterial lipopolysaccharide (LPS) down to 46% after 30 min with 96 mu M KTP-NH2-DL. The same molecule has lower ability to permeate membranes (relative permeability of 0.38) and no significant activity in a behavioral test which evaluates thermal nociception (hot-plate test). On the contrary, methylated isomers at 96 mu M increase leukocyte rolling up to nearly 5-fold after 30 min, suggesting a proinflammatory activity. They have maximal ability to permeate membranes (relative permeability of 0.8) and induce long-lasting antinociception
Texto completo:
1
Colección:
06-national
/
BR
Base de datos:
SES-SP
/
SESSP-IBPROD
Asunto principal:
Farmacología
/
Alergia e Inmunología
/
Anestesiología
Revista:
ACS Chem. Neurosci
Año:
2016
Tipo del documento:
Article