1,5-Benzodiazepine tricyclic derivatives exerting anti-inflammatory effects in mice by inhibiting interleukin-6 and prostaglandin E2 production

Paolo Fruscella, Marcello Sottocorno, Mario Di Braccio, Luisa Diomede, Nicola Piccardi, Alfredo Cagnotto, Giancarlo Grossi, Maria Romano, Tiziana Mennini, Giorgio Roma

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The 1,4- and the 1,5-benzodiazepines (BDZ) are commonly used as anxiolytic and anticonvulsive drugs. It has been suggested that they influence, particularly through stimulation of peripheral BDZ receptors, some immune cell properties such as pro-inflammatory cytokine production. The availability of a new class of [1,2,4]triazolo[4,3-a][1,5]benzodiazepine derivatives (compounds IV), endowed with anti-inflammatory and/or analgesic properties but no anti-pentylenetetrazole activity, prompted us to investigate in more detail the anti-inflammatory properties of three selected compounds IV (N,N-dimethyl-1-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine-5-amine; N,N-dibutyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine-5-amine; 1-methyl-N,N-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine-5-amine) and one structurally related compound (1-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine-5(6H)-one). These BDZ derivatives have lost their affinity for the central and peripheral BDZ receptors. The in vivo effect on leukocyte migration of these compounds was investigated by using the mouse air-pouch model of local inflammation. Compounds A and B, significantly inhibited the carrageenan-induced leukocyte recruitment in a dose-dependent manner starting from the dose of 50 mg kg-1, whereas compound C was effective only at the higher dose of 100 mg kg-1. Compound D did not exert such effects at any of the doses considered. The effect of compounds A, B and C on leukocyte recruitment was paralleled by a significant inhibition of interleukin-6 and prostaglandin E2 production in the exudate, similarly to indomethacin, and by a partial reduction of vascular permeability. These features may be relevant for the design and development of innovative anti-inflammatory molecules among the 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine-5-amine derivatives.

Original languageEnglish
Pages (from-to)445-451
Number of pages7
JournalPharmacological Research
Issue number5
Publication statusPublished - 2001


  • IL-6
  • Inflammation
  • PGE
  • Triazolo-benzodiazepine

ASJC Scopus subject areas

  • Pharmacology


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