F. Rohet et al., SYNTHESIS AND ANALGESIC EFFECTS OF 3-SUBSTITUTED 4,6-DIARYLPYRIDAZINEDERIVATIVES OF THE ARYLPIPERAZINE CLASS, Bioorganic & medicinal chemistry, 5(4), 1997, pp. 655-659
A new series of 4,6-diaryl pyridazines substituted in the 3-position b
y arylpiperazinyl moieties was synthesized and evaluated for analgesic
activity. Five out of the nine tested compounds possessed significant
antinociceptive effects in the phenylbenzoquinone-induced writhing te
st (PBQ test) with ED50 values ranging from 26.0 to 37.7 mg/kg ip. The
most active derivatives 2a, 2d and 2h had a low toxicity (LD50 > 800
mg/kg ip) but showed some sedative and neurotoxic effects from the dos
e of 50 mg/kg ip. The three selected pyridazines were devoid of activi
ty in the hot-plate test. However, analgesic activity of 2d and 2h was
significantly reversed by naloxone in the PBQ test. Administered at t
he low dose of 5 mg/kg ip, 2h greatly potentiated the antinociceptive
response induced by morphine (0.15 mg/kg sc). In addition, analgesic e
ffects of 2h (2.5 mg/kg ip) were also potentiated by 5-hydroxytryptoph
an combined with carbidopa. These results suggest that pyridazine 2h i
nduces analgesia, which is mediated via both opioid and serotonergic m
echanisms. (C) 1997 Elsevier Science Ltd.