A series of 4,6-diaryl pyridazinones, chemically related to trazodone, ws synthesized and evaluated for analgesic activity. With ED50 values ranging from 8.4 to 46.7 mg kg(-1) i.p. in the phenylbenzoquinone-induced writhing test (PBQ test), most compounds were several times more potent than acetaminophen (ED50 = 231.3 mg kg(-1) i.p.) and noramidopyrine (ED50 = 68.5 mg kg(-1) i.p.). A multiple linear regression analysis demonstrated a correlation between antinociceptive activity and lipophilicity, as well as electronic and steric factors. The most active pyridazinones 2c and 2j exhibited minimal sedative and neurotoxic effects at the dose of 25 mg kg(-1) i.p. They were devoid of activity in the hot plate test and their analgesic activity was not significantly reversed by naloxone in the PBQ test. The antinociceptive response induced by morphine (0.15 mg kg(-1) s.c.) in the PBQ test was greatly potentiated by 2c and 2j administered at the low doses of 1 and 2.5 mg kg(-1) i.p., respectively. On the other hand, their analgesic effects were enhanced synergistically by 5-hydroxytryptophan combined with carbidopa. All these data imply that a significant part of the antinociceptive effect induced by 2c and 2j may involve both opioid and serotonergic pathways. In addition, these two pyridazinones did not exhibit any antidepressant properties in the forced swimming test, nor did they potentiate yohimbine-induced toxicity.

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A new series of 4,6-diaryl pyridazin-3-ones substituted on the nitrogen atom in the 2position have been prepared and evaluated for their analgesic activity in the phenylbenzoquinone-induced abdominal constriction test.Most of the eighteen compounds displayed signi®cant antinociceptive effects with ED50 ranging from 22Á2 to 76Á7 mg kg À1 , intraperitoneally. Pyridazinones 4f and 5f were among the most interesting derivatives with marked analgesic properties associated to weak neurosedative activities (ED50 83Á3 and 247Á2 mg kg À1 , i.p., respectively).Further investigations provided support for the hypothesis that the antinociceptive action of 4f and 5f probably resulted from interactions with opioidergic, 5-hydroxytryptaminergic and noradrenergic pathways.Correspondence: P. Coudert, Laboratoire de Chimie The Ârapeutique, Faculte  de Pharmacie, 28 place H. Dunant, 63001 Clermont-Ferrand Cedex, France.

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