title: Pharmacological properties and SAR of new 1,4-disubstituted piperazine derivatives with hypnotic-sedative activity.
abstract: Preparation, pharmacological properties and structure-activity relationships of new pyrimidyl-piperazine derivatives, exhibiting sedative and hypnotic activity in mice, are reported. The hypnotic activity of the compounds was comparable with that of zopiclone (the known hypnotic-sedative agent), their interaction with ethanol, however, being much lower. The obtained results suggested that zopiclone and pyrimidylpiperazines 2, 4 and 5 exerted their pharmacological activity through a different mechanism - zopiclone through the interaction with benzodiazepine receptors and compounds 2, 4 and 5 through an unidentified molecular target. The pharmacological properties of compound 3 could be the result of a mixed mechanism of action, combining the properties of zopiclone and those of compounds 2, 4 and 5. A common feature of zopiclone and compounds 2 and 3 was that, after their systemic administration, independently of mechanism of action, together with the hypnotic effect a reduction of the 5-HT turnover in the mouse brain was observed. Minimum structural requirements for the hypnotic activity were formulated. Structural considerations have shown that removing the alpha-carbonyl group did not influence the drug's ability to inhibit the locomotor activity. However, it did influence its ability to disturb motor coordination or abolish the righting reflex within non-lethal doses.
authors: Drug Institute, Warszawa, Poland. chilmon@il.waw.pl
authors: Zdzisław
authors: Z
authors: Chilmonczyk
authors: Maria
authors: M
authors: Mazgajska
authors: Joanna
authors: J
authors: Iskra-Jopa
authors: Ewa
authors: E
authors: Chojnacka-Wójcik
authors: Ewa
authors: E
authors: Tatarczyńska
authors: Aleksandra
authors: A
authors: Kłodziriska
authors: Jerzy Z
authors: JZ
authors: Nowak
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D006993:Hypnotics and Sedatives / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D012701:Serotonin / Q000032:analysis; D013329:Structure-Activity Relationship
chemical_list: D006993:Hypnotics and Sedatives; D010879:Piperazines; D018079:Receptors, GABA; D017981:Receptors, Neurotransmitter; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid