Pharmacological properties and SAR of new 1,4-disubstituted piperazine derivatives with hypnotic-sedative activity

• Published in: Journal of pharmacy and pharmacology 2002-05, Vol.54 (5), p.689-698
• Main Authors: Chilmonczyk, Zdzislaw, Mazgajska, Maria, Iskra-Jopa, Joanna, Chojnacka-Wójcik, Ewa, Tatarczyńka, Ewa, Klodzińska, Aleksandra, Nowak, Jerzy Z.
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Biological and medical sciences; Brain Chemistry - drug effects; Chromatography, High Pressure Liquid; Hydroxyindoleacetic Acid - analysis; Hypnotics and Sedatives - chemistry; Hypnotics and Sedatives - pharmacology; Hypnotics and Sedatives - toxicity; Hypnotics. Sedatives; Lethal Dose 50; Male; Medical sciences; Mice; Neuropharmacology; Pharmacology. Drug treatments; Piperazines - chemistry; Piperazines - pharmacology; Piperazines - toxicity; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Rats, Wistar; Receptors, GABA; Receptors, Neurotransmitter - metabolism; Serotonin - analysis; Structure-Activity Relationship
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1211/0022357021778844

Preparation, pharmacological properties and structure‐activity relationships of new pyrimidylpiperazine 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 α‐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.