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 (PC13), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125.8 and 429.6 mg kg-1. Only at intraperitoneal doses of 100 mg 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 forces 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 PC13 (20 mg 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 (100 mg 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 (5.0 < ED50 < 5.5 mg kg-1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg-1, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)
Rubat
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Laboratoire de Pharmacologie et de Pharmacie Clinique, Clermont-Ferrand, France.
Coudert
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Bastide
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Tronche
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D006916:5-Hydroxytryptophan / Q000633:toxicity; D000698:Analgesia; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000008:administration & dosage / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects*; D001763:Blepharoptosis / Q000517:prevention & control; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002997:Clomipramine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004347:Drug Interactions; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007035:Hypothermia / Q000139:chemically induced; D007099:Imipramine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000008:administration & dosage / Q000633:toxicity; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011724:Pyridazines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D012110:Reserpine / Q000008:administration & dosage / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013550:Swimming; D014196:Trazodone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015016:Yohimbine / Q000008:administration & dosage / Q000633:toxicity
C094453:5-benzyl-6-methyl-2-(4-(3-chlorophenyl)piperazin-1-yl)methylpyridazin-3-one; C094452:5-benzyl-6-methyl-2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)methylpyridazin-3-one; D000928:Antidepressive Agents; D010879:Piperazines; D011724:Pyridazines; D005473:Fluoxetine; D015283:Citalopram; D015016:Yohimbine; D009270:Naloxone; D012110:Reserpine; D006916:5-Hydroxytryptophan; D001058:Apomorphine; D002997:Clomipramine; D007099:Imipramine; D014196:Trazodone