Behavioural Profile of Two Potential Antidepressant Pyridazine Derivatives Including Arylpiperazinyl Moieties in Their Structure,in Mice

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PCI3), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125·8 and 429-6mg kg^?1. Only at intraperitoneal doses of 100mg kg^?1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5–20 mg kg^?1, i.p.) reduced the duration of immobility of mice in the forced swimming test, antagonized reserpine (2–5 mg kg^?1, i.p.)-induced ptosis, and potentiated reserpine (2–5 mg kg^?1, i.p.)-induced hypothermia. PC4 and PCI3 (20mg kg^?1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg^?1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg^?1, s.c). At 200 mg kg^?1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg^?1, s.c), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg^?1, i.p.) in mice pretreated with pargyline (100mg kg^?1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg^?1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg^?1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (50 < ED50 < 5-5mg kg^?1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg^?1, i.p.). These antinociceptive effects were not significantly diminished by naloxone (1 mg kg^?1, i.p.). Furthermore, acute intraperitoneal administration of both compounds (20 mg kg^?1 for PC4 and 5mg kg^?1 for PC13) potentiated morphine (7–5 mg kg^?1, s.c.) analgesia in the hot-plate test. Thus, these results suggest that PC4 and PC 13 possess potential antidepressant effects related to different aminergic mechanisms, especially at the 5-HT₂ receptor level.