Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenyl-N-acylhydrazone derivatives: Discovery of LASSBio-881, a new ligand of cannabinoid receptors.
We describe herein the discovery of LASSBio-881 (3c) as a novel in vivo antinociceptive, anti-inflammatory, and in vitro antiproliferative and antioxidant compound, with a cannabinoid ligand profile. We observed that LASSBio-881 (3c) was able to bind to CB1 receptors (71% at 100microM) and also to inhibit T-cell proliferation (66% at 10microM) probably by binding to CB2 receptors, in a non-proapoptotic manner, different from anandamide (1). It was also demonstrated that LASSBio-881 (3c) had an important antioxidant profile toward free radicals (DPPH and hydroxyl), probably due to its particular redox behavior, which reflects the presence of both nitro and 3,5-di-tert-butyl-4-hydroxyphenyl sub-units, as demonstrated by cyclic voltammetry studies. In addition, we showed that these structural sub-units are essential for the observed pharmacological activity.
Duarte
Carolina D
CD
LASSBio--Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68006, 21944-971, Rio de Janeiro, RJ, Brazil.
Tributino
Jorge L M
JL
Lacerda
Daniel I
DI
Martins
Marina V
MV
Alexandre-Moreira
Magna S
MS
Dutra
Fernando
F
Bechara
Etelvino J H
EJ
De-Paula
Francine S
FS
Goulart
Marilia O F
MO
Ferreira
Juliano
J
Calixto
João B
JB
Nunes
Marise P
MP
Bertho
Alvaro L
AL
Miranda
Ana Luisa P
AL
Barreiro
Eliezer J
EJ
Fraga
Carlos A M
CA
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000633:toxicity; D001095:Arachidonic Acids / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000378:metabolism; D001921:Brain / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002351:Carrageenan / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D063388:Endocannabinoids; D005260:Female; D005557:Formaldehyde / Q000633:toxicity; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010146:Pain / Q000188:drug therapy; D010851:Picrates; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D016166:Free Radical Scavengers; D006834:Hydrazines; D006835:Hydrazones; C518927:LASSBio-881; D008024:Ligands; D010851:Picrates; D053284:Polyunsaturated Alkamides; D011725:Pyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C431843:tris(2-pyridylmethyl)amine; D013481:Superoxides; D005557:Formaldehyde; D016718:Arachidonic Acid; D002351:Carrageenan; C004931:1,1-diphenyl-2-picrylhydrazyl; C078814:anandamide