title: Endothelium-Mediated Action of Analogues of the Endogenous Neuropeptide Kyotorphin (Tyrosil-Arginine): Mechanistic Insights from Permeation and Effects on Microcirculation.
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 μM 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 μM 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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Juliana
authors.initials: J
authors.lastname: Perazzo
authors.affiliation: Unidade de Imunorregulação, Laboratório Especial de Toxinologia Aplicada, Instituto Butantan , Av. Vital Brasil, 1500 São Paulo, Brazil.
authors.forename: Mônica
authors.initials: M
authors.lastname: Lopes-Ferreira
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Sónia
authors.initials: S
authors.lastname: Sá Santos
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Isa
authors.initials: I
authors.lastname: Serrano
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Antónia
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Unidade de Imunorregulação, Laboratório Especial de Toxinologia Aplicada, Instituto Butantan , Av. Vital Brasil, 1500 São Paulo, Brazil.
authors.forename: Carla
authors.initials: C
authors.lastname: Lima
authors.affiliation: Laboratori d'Innovació en processos i Productes de Síntesi Orgànica (LIPPSO), Department de Química, Universitat de Girona , Campus Montilivi, 17071 Girona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Bardaji
authors.affiliation: Instituto de Biologia Molecular e Celular , Rua do Campo Alegre, 4150-180 Porto, Portugal.|i3S - Instituto de Inovação e Investigação em Saúde, and Departamento de Biologia Experimental, Faculdade de Medicina, Universidade do Porto , 4099-002 Porto, Portugal.
authors.forename: Isaura
authors.initials: I
authors.lastname: Tavares
authors.affiliation: Laboratori d'Innovació en processos i Productes de Síntesi Orgànica (LIPPSO), Department de Química, Universitat de Girona , Campus Montilivi, 17071 Girona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Heras
authors.affiliation: Departamento de Ciência e Tecnologia, Universidade Federal de São Paulo, UNIFESP , Rua Talim, 330, 04021-001 São José dos Campos, Brazil.
authors.forename: Katia
authors.initials: K
authors.lastname: Conceição
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Miguel A R B
authors.initials: MA
authors.lastname: Castanho
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents; D001812:Blood-Brain Barrier; D004150:Dipeptidases / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004723:Endorphins / Q000737:chemistry* / Q000494:pharmacology; D004727:Endothelium / Q000187:drug effects*; D006930:Hyperalgesia / Q000188:drug therapy; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects*; D051381:Rats; D013997:Time Factors
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D004723:Endorphins; C019448:kyotorphin; D004150:Dipeptidases; C073383:kyotorphin I dipeptidase
keywords: Kyotophin; analgesia; blood-brain barrier; microcirculation; pain; permeability