Synthesis of peripherally acting analgesic 3-arylpiperazinyl-5-benzyl-pyridazines

A series of 3-arylpiperazinyl-5-benzyl-pyridazines was synthesized and evaluated for analgesic activity. The structures of these new pyridazine derivatives were confirmed by IR, 1H-NMR spectra and by elementary analysis. With ED50 values ranging from 6.0 to 71.5 mg/kg i.p. most of the compounds were several times more potent than acetaminophen (ED50 = 228.6 mg/kg i.p.) and noramidopyrine ((ED50 = 68.8 mg/kg i.p.) in the phenylbenzoquinone-induced writhing test (PBQ-test). Quantitative structure-activity relationships were accomplished by a Hansch analysis. The most active pyridazines 2h-j exhibited sedative properties from the dose of 25 mg/kg i.p. Their lack of activity in the hot plate test was in favour of peripherally acting agents. In the PBQ test, analgesic activity of 2h-j was antagonized by naloxone. However, their antinociceptive effect added up to those of 5-hydroxytryptophan when given in association with carbidopa. These results demonstrated that analgesic properties of pyridazine derivatives might involve a serotonergic pathway without interaction with opiodergic systems.