Synthesis and analgesic effects of 5-[4-(arylpiperazin-1-yl)alkylamino]-4-benzyl-3-methyl-1,2-oxazin-6-ones

A series of 5-[4-(arylpiperazin-1-yl)alkylamino]-4-benzyl-3-methyl-1,2-oxaz in-6-ones was synthesized and evaluated for analgesic activity. The structu res of these new oxazine derivatives were confirmed by IR,H-1-NMR spectra a nd by elemental analysis. The three most active compounds, 3c, 3e and 3g po ssessed significant antinociceptive effects in the phenylbenzoquinone-induc ed wrigthing test (PBQ-test) in mice, with ED50 values ranging from 19.7 to 68.0 mg/kg i.p. In addition these compounds presented a low toxicity (LD50 > 800 mg/kg i.p.) and did not significantly reduce the spontaneous locomot or activity of mice. They interacted in a synergistic manner with morphine but nevertheless each compound presented its own profile. Thus the analgesi c activity of 3e and 3e was naloxone sensitive, suggesting in mu opioidergi c mechanism. Otherwise 3e and 3d analgesia was attenuated by oral administr ation of yohimbine and therefore seemed to be mediated via noradrenergic pa thway. Finally, 5-hydroxytryptophan associated to carbidopa only potentiate d 3e analgesia, demonstrating an involvement of a serotoninergic mechanism.