Effects of Two N-arylpiperazinylmethylpyrazolo [1,5-d][1,2,4]triazine Derivatives in Pain and Antidepressant Tests in Mice

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 SMI and SM3 were 253-4 and 218.8mg kg- respectively. SMI and SM3 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (ED50 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 3.2mg kg -1 , s.c.) and yohimbine (1mgkg -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 mgkg -1 , s.c.) analgesia in the phenylbenzoquinone test. Although this synergistic activity was not reversed by methysergide (0.5 mgkg -1 , i.p.), the analgesic activity of both compounds was enhanced by administration of 5-hydroxytryptophan (50mg kg -1 , i.p.) in conjunction with carbidopa (25mgkg -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 75mg kg -1 , i.p.) were ineffective at enhancing the toxic effects of yohimbine (30mg kg -1 , s.c.). Only SM3 (ED50 = 74.5 mgkg -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 α 2 -adrenoceptor mechanisms without associated antidepressant properties.