SYNTHESIS AND TRAZODONE-LIKE ANALGESIC ACTIVITY OF 2-[3-(4-ARYLPIPERAZIN-1-YL)PROPYL]PYRIDAZIN-3-ONES

A series of 4,6-diaryl pyridazinones, chemically related to trazodone, was synthesized and evaluated for analgesic activity. With ED(50) val ues ranging from 8.3 to 46.7 mg kg(-1) i.p. in the phenylbenzoquinone- induced writhing test (PBQ test), most compounds were several times mo re potent than acetaminophen (ED(50) = 231.3 mg kg(-1) i.p.) and noram idopyrine (ED(50) = 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 neurotox ic effects at the dose of 25 mg kg(-1) i.p. They were devoid of activi ty in the hot plate test and their analgesic activity was not signific antly reversed by naloxone in the PBQ test. The antinociceptive respon se induced by morphine (0.15 mg kg(-1) s.c.) in the PBQ test was great ly 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 effe cts were enhanced synergistically by 5-hydroxytryptophan combined with carbidopa. All these data imply that a significant part of the antino ciceptive effect induced by 2c and 2j may involve both opioid and sero tonergic pathways, In addition, these two pyridazinones did not exhibi t any antidepressant properties in the forced swimming test, nor did t hey potentiate yohimbine-induced toxicity.