Behavioural profile of two potential antidepressant pyridazine derivatives including arylpiperazinyl moieties in their structure, in mice

• Published in: Journal of pharmacy and pharmacology Vol. 47; no. 2; p. 162
• Main Authors: Rubat, C, Coudert, P, Bastide, P, Tronche, P
• Format: Journal Article
• Language: English
• Published: England 01.02.1995
• Subjects: 5-Hydroxytryptophan - toxicity; Analgesia; Animals; Antidepressive Agents - pharmacology; Apomorphine - administration & dosage; Apomorphine - toxicity; Behavior, Animal - drug effects; Blepharoptosis - prevention & control; Citalopram - administration & dosage; Citalopram - pharmacology; Citalopram - therapeutic use; Clomipramine - administration & dosage; Clomipramine - pharmacology; Clomipramine - therapeutic use; Drug Interactions; Fluoxetine - administration & dosage; Fluoxetine - pharmacology; Fluoxetine - therapeutic use; Hypothermia - chemically induced; Imipramine - administration & dosage; Imipramine - pharmacology; Imipramine - therapeutic use; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Models, Molecular; Motor Activity - drug effects; Naloxone - administration & dosage; Naloxone - toxicity; Piperazines - administration & dosage; Piperazines - pharmacology; Piperazines - therapeutic use; Pyridazines - administration & dosage; Pyridazines - chemistry; Pyridazines - pharmacology; Pyridazines - therapeutic use; Reserpine - administration & dosage; Reserpine - pharmacology; Structure-Activity Relationship; Swimming; Trazodone - administration & dosage; Trazodone - pharmacology; Trazodone - therapeutic use; Yohimbine - administration & dosage; Yohimbine - toxicity
• ISSN: 0022-3573
• DOI: 10.1111/j.2042-7158.1995.tb05771.x

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.).