1,5-benzodiazepine tricyclic derivatives exerting anti-inflammatory effects in mice by inhibiting interleukin-6 and prostaglandin E-2 production

The 1,4- and the 1,5-benzodiazepines (BDZ) are commonly used as anxiolytic and anticonvulsive drugs. It has been suggested that they influence, partic ularly through stimulation of peripheral BDZ receptors, some immune cell pr operties such as pro-inflammatory cytokine production. The availability of a new class of [1,2,4]triazolo[4,3-a] [1,5]benzodiazepine derivatives (comp ounds IV), endowed with anti-inflammatory and/or analgesic properties but n o antipentylenetetrazole activity, prompted us to investigate in more detai l the anti-inflammatory properties of three selected compounds IV (N,N-dime thyl-1-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amine; N,N-dibu tyl-4H-[1,2,4]triazolo[4,3-a] [1,5]benzodiazepin-5-amine; 1-methyl-N,N-dime thyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amine) and one structura lly related compound (1-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin- 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 loca l 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 d ose of 100 mg kg(-1). Compound D did not exert such effects at any of the d oses considered. The effect of compounds A, B and C on leukocyte recruitmen t was paralleled by a significant inhibition of interleukin-6 and prostagla ndin E-2 production in the exudate, similarly to indomethacin, and by a par tial reduction of vascular permeability, These features may be relevant for the design and development of innovative anti-inflammatory molecules among the 4H-[I,2,4]triazolo[4,3-a] [1.5]benzodiazepin-5-amine derivatives. (C) 2001 Academic Press.