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.

Biological evaluation of 10-(diphenylmethylene)- 4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives

“…Inserting selected piperazine moieties into the oxypropanolamine side chain increases the antagonistic α 1 -adrenergic properties [5,6]. Arylpiperazine derivatives of this group also confer intraocular pressure lowering effects [7] and display considerable affinity for the serotonergic 5-HT receptors [8,9]. It was suggested that the isopropanolamine unit present in peptidic drugs (e.g.…”