title: Effects of CI-926 (3-[4-[4-(3-methylphenyl)-1-piperazinyl] butyl]-2,-4-imidazolidinedione), an antihypertensive agent, on rat brain catecholamine and serotonin turnover.
abstract: The effects of the antihypertensive drug CI-926 on rat brain norepinephrine (NE), dopamine (DA), and serotonin (5-HT) turnover and its in vitro affinity for several receptors were investigated. CI-926 (3-30 mg/kg intraperitoneally, i.p.) caused a dose-dependent increase in the rate of brain stem NE synthesis and increased the decline in NE after inhibition of its synthesis by alpha-methyl-p-tyrosine. These findings indicated that CI-926 increased brain NE turnover, probably as a compensatory response to central adrenoceptor blockade based on its nanomolar affinity for alpha 1-adrenoceptors and micromolar affinity for alpha 2-adrenoceptors. CI-926 also increased the rate of DA synthesis and DA metabolite levels; this indicates an increase in DA turnover. The latter effect of CI-926 is attributed to a compensatory response to DA-2 receptor blockade because no affinity for DA-1 relative to DA-2 receptors was found and the effect was antagonized by the DA agonist pergolide. CI-926 decreased brain 5-HT turnover, as indicated by reduced concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid and a reduced rate of 5-HT synthesis, effects characteristic of centrally acting 5-HT agonists. Based on its affinity for 5-HT-1A receptors versus 5-HT-1B and 5-HT-2, the decrease in 5-HT synthesis and release is interpreted as evidence of 5-HT-1A receptor activation. These findings indicate that besides peripheral alpha 1-adrenergic blockade, an interference of CI-926 with central adrenergic and serotoninergic neurotransmission may contribute in part to an explanation of its antihypertensive properties.
authors: Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
authors: T A
authors: TA
authors: Pugsley
authors: S M
authors: SM
authors: Myers
authors: Y H
authors: YH
authors: Shih
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002395:Catecholamines / Q000096:biosynthesis / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000959:Antihypertensive Agents; D002395:Catecholamines; D007093:Imidazoles; D010879:Piperazines; C048884:CI 926; D012701:Serotonin; C015568:urapidil; D004298:Dopamine; D009638:Norepinephrine