title: Synthesis, toxicity study and anti-inflammatory effect of MHTP, a new tetrahydroisoquinoline alkaloid.
abstract: The alkaloid 2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenol (MHTP) was synthesized to prospect new compounds with therapeutic properties. Thus, the goal of this study was to evaluate the MHTP anti-inflammatory effect by in vivo and in vitro assays. The MHTP toxicity was analyzed. We found that MHTP pre-treatment (2.5-10 mg/kg) showed antiedematogenic effect (p < 0.05) in carrageenan-induced paw edema by inhibiting the PGE2 action independently of mast cell degranulation or histamine activity. MHTP also diminished (p < 0.01) total leukocyte migration in 41.5% into peritoneal cavity during carrageenan-induced peritonitis, reducing polymorphonuclear cells (PMNs) (59.6%) and proteins levels (29.4%). MHTP in an experimental model of acute lung injury inhibited (p < 0.001) total inflammatory cell migration into the lungs and PMNs in 58% and 67.5%, respectively. Additionally, MHTP did not present cytotoxicity at concentrations of 10, 25 or 50 μM but decreased (p < 0.001) the NO production in 24%, 47% and 39%, respectively. The alkaloid also reduced (p < 0.001, in lipopolysaccharide (LPS)-stimulated macrophages (1 μg/mL), IL-1β, IL-6 and IL-10 levels in 35.7%, 31.0% and 33.4%, respectively. The results obtained in this study allow us to conclude that the inedited synthetic alkaloid, MHTP has anti-inflammatory effect by inhibiting PGE2 function as well as inhibiting inflammatory cell migration to the inflamed site and attenuated the acute lung injury disease by inhibiting the migration of neutrophil to the lung. However, further studies will be carried out to demonstrate the mechanisms of action of the molecule and explore its potential as a future drug to treat inflammatory processes.
authors.affiliation: Centro de Ciências Exatas e da Natureza, Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal da Paraíba , João Pessoa, Paraíba , Brasil .
authors.forename: Maria Talita
authors.initials: MT
authors.lastname: Pacheco de Oliveira
authors.forename: Theresa Raquel
authors.initials: TR
authors.lastname: de Oliveira Ramalho
authors.forename: Laércia Karla Liege
authors.initials: LK
authors.lastname: Paiva Ferreira
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Araújo Lima
authors.forename: Manuela
authors.initials: M
authors.lastname: Barbosa Cordeiro
authors.forename: Hermann
authors.initials: H
authors.lastname: Ferreira Costa
authors.forename: Luís Cézar
authors.initials: LC
authors.lastname: Rodrigues
authors.forename: Marcia Regina
authors.initials: MR
authors.lastname: Piuvezam
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000276:immunology; D000470:Alkaloids / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy / Q000276:immunology; D005260:Female; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D010538:Peritonitis / Q000188:drug therapy / Q000276:immunology; D061251:Primary Cell Culture; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D023382:Toxicity Tests, Acute
chemical_list: C000607450:2-methoxy-4-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenol; D000470:Alkaloids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D044005:Tetrahydroisoquinolines
keywords: Acute inflammation; acute lung injury; anti-inflammatory; synthetic alkaloid