SYNTHESIS AND PHARMACOLOGICAL EVALUATION IN MICE OF NEW NONCLASSICAL ANTINOCICEPTIVE AGENTS, -(4-ARYLPIPERAZIN-1-YL)-4-BENZYL-1,2-OXAZIN-6-ONES

Several -(4-aryIpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones have been s ynthesized and tested for analgesic activity in a visceral pain model (phenylbenzoquinone-induced writhing test=PBQ test), ii good correlati on has been found between the antinociceptive effects of drugs and bot h their Lipophilic and steric properties, The most active derivatives 5c and 5f, with intraperitoneal ED50 values of 10.5 and 10.3 mg kg(-1) respectively, were more extensively investigated by evaluating their analgesic activity in a somatosensory pain model (hot plate test), as well as their sedative properties, Furthermore, naloxone suppressed th e effect of 5c and 5f in the PBQ test, though these derivatives were i neffective to potentiate morphine analgesia, Pretreatment with yohimbi ne did not significantly attenuate the analgesic effects of 5c and 5f, In addition, pretreatment with 5-hydroxytryptophan associated with ca rbidopa also failed to potentiate the antinociceptive effects of 5c an d 5f, So, a part of the analgesic activity of 5c and 5f seems to be re lated to an opioidergic mechanism, especially at the mu receptor level , Molecular modeling studies performed on the opiate drug morphine and on the most stable conformer of 5f showed structural similarities bet ween these two molecules.