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.
Moreau
S
S
Groupe de Recherches en Pharmacochimie, Laboratoire de Chimie Thérapeutique, Université d'Auvergne, Clermont-Ferrand, France.
Coudert
P
P
Rubat
C
C
Albuisson
E
E
Couquelet
J
J
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D004357:Drug Synergism; D008297:Male; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014196:Trazodone / Q000494:pharmacology
D018712:Analgesics, Non-Narcotic; D018687:Antidepressive Agents, Second-Generation; D001593:Benzyl Compounds; D009292:Narcotic Antagonists; D011724:Pyridazines; D009270:Naloxone; D006916:5-Hydroxytryptophan; D014196:Trazodone