Synthesis and analgesic effects of 3-substituted 4,6-diarylpyridazine derivatives of the arylpiperazine class.
A new series of 4,6-diaryl pyridazines substituted in the 3-position by 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 test (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 dose of 50 mg/kg ip. The three selected pyridazines were devoid of activity in the hot-plate test. However, analgesic activity of 2d and 2h was significantly reversed by naloxone in the PBQ test. Administered at the low dose of 5 mg/kg ip, 2h greatly potentiated the antinociceptive response induced by morphine (0.15 mg/kg sc). In addition, analgesic effects of 2h (2.5 mg/kg ip) were also potentiated by 5-hydroxytryptophan combined with carbidopa. These results suggest that pyridazine 2h induces analgesia, which is mediated via both opioid and serotonergic mechanisms.
Rohet
F
F
Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Université d'Auvergne, Clermont-Ferrand, France.
Rubat
C
C
Coudert
P
P
Couquelet
J
J
D000082:Acetaminophen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016227:Benzoquinones / Q000008:administration & dosage / Q000633:toxicity; D004177:Dipyrone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004347:Drug Interactions; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins / Q000009:adverse effects; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D047069:Pyrazolones; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism; D012015:Reference Standards; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014196:Trazodone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D016227:Benzoquinones; D004177:Dipyrone; D009020:Morphine; D009270:Naloxone; D009292:Narcotic Antagonists; D009498:Neurotoxins; D047069:Pyrazolones; D011724:Pyridazines; D011957:Receptors, Opioid; D017367:Selective Serotonin Reuptake Inhibitors; D014196:Trazodone; C029322:phenylbenzoquinone; C008667:noramidopyrine