title: Effects of two N-arylpiperazinylmethylpyrazolo [1,5-d][1,2,4]triazine derivatives in pain and antidepressant tests in mice.
abstract: The antinociceptive and antidepressant effects of two pyrazolotriazine derivatives, 2-phenyl-3,3a-dihydro-4-oxo-5-(4-phenylpiperazin-1-yl) methyl-pyrazolo[1,5-d][1,2,4]-triazine (SM1) and 2-phenyl-3,3a-dihydro-4-oxo-5-[4-(4-fluorophenyl)piperazin-1-yl] methylpyrazolo[1,5-d][1,2,4] triazine (SM3) have been investigated in mice using classical pharmacological tests. The intraperitoneal LD50 values of SM1 and SM3 were 253.4 and 218.8 mg kg-1 respectively. SM1 and SM3 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (ED50 approximately 10-15 mg kg-1, i.p.) and in the hot-plate test. The antinociceptive effects of the triazines were significantly reduced by administration of naloxone (1 and 3.2 mg kg-1, s.c.) and yohimbine (1 mg kg-1, p.o.). Acute intraperitoneal administration of both compounds (1 mg kg-1 SM1 or 1.5 mg kg-1 SM3) potentiated morphine (0.15 mg kg-1, s.c.) analgesia in the phenylbenzoquinone test. Although this synergistic activity was not reversed by methysergide (0.5 mg kg-1, i.p.), the analgesic activity of both compounds was enhanced by administration of 5-hydroxytryptophan (50 mg kg-1, i.p.) in conjunction with carbidopa (25 mg kg-1, i.p.). Furthermore, neither compound (at 100 mg kg-1, i.p.) significantly reduced the duration of immobility of mice in the forced swimming test, and both (at 75 mg kg-1, i.p.) were ineffective at enhancing the toxic effects of yohimbine (30 mg kg-1, s.c.). Only SM3 (ED50 = 74.5 mg kg-1, i.p.) significantly antagonized reserpine (2.5 mg kg-1, i.p.)-induced ptosis. Thus, the results suggest that SM1 and SM3 have antinociceptive properties related to co-involvement of opioidergic and alpha 2-adrenoceptor mechanism without associated antidepressant properties.
authors.affiliation: Laboratoire de Pharmacologie, UFR de Pharmacie, Clermont-Ferrand, France.
authors.forename: C
authors.initials: C
authors.lastname: Rubat
authors.forename: P
authors.initials: P
authors.lastname: Coudert
authors.forename: S
authors.initials: S
authors.lastname: Mavel
authors.forename: J
authors.initials: J
authors.lastname: Fialip
authors.forename: J
authors.initials: J
authors.lastname: Couquelet
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology / Q000633:toxicity; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004347:Drug Interactions; D007103:Immobilization; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology* / Q000633:toxicity; D011930:Reaction Time / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology* / Q000633:toxicity; D015016:Yohimbine / Q000494:pharmacology / Q000633:toxicity
chemical_list: C110190:2,2-phenyl-3,3a-dihydro-4-oxo-5-(4-phenylpiperazin-1-yl)methylpyrazolo(1,5-d)(1,2,4)triazine; C110139:2-phenyl-3,3a-dihydro-4-oxo-5-(4-(4-fluorophenyl)piperazin-1-yl)methylpyrazolo(1,5-d)(1,2,4)trazine; D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D000701:Analgesics, Opioid; D000928:Antidepressive Agents; D002492:Central Nervous System Depressants; D009292:Narcotic Antagonists; D011720:Pyrazoles; D012702:Serotonin Antagonists; D014227:Triazines; D015016:Yohimbine; D009020:Morphine