Anxiolytic Properties of 1-Aryl-4-(phthalimidoalkyl)piperazines and Their Affinity to 5-HT1A Serotonin and D2 Dopamine Receptors

Abstract

Established in the late 1980s, the important role of 5-HT1A receptors in the pathogenesis of anxiety states and depressions has stimulated extensive search for the corresponding selective ligands. Among the known compounds possessing a high affinity to 5-HT1A receptors, the most thoroughly studied are aryl(hetaryl)piperazine derivatives. Although many of these substances possess anxiolytic properties [1, 2], only buspirone and gepirone – partial agonists of 5-HT1A receptors – are now used in clinical practice. The main factors limiting administration of these drugs in clinics is their low bioaccessibility, large delay (sometimes up to 2 – 6 weeks [3, 4]) in the therapeutic effect, and relatively high affinity to adrenaline ( 1, 2, 2), dopamine (D2), and other CNS receptors [1, 2, 5 – 9]. The low selectivity of aryl(hetaryl)piperazines is explained by the fact that the 5-HT1A serotonin, D2 dopamine, and 1 adrenaline receptors are “evolutionarily” close and belong to the same superfamily of G-protein-conjugated receptors. Indeed, an analysis of the primary amino acid sequences confirms the highly homologous character of these receptors [1]. Nevertheless, some highly selective ligands to 5-HT1A receptors have been found, such as (S)-UH-301 [10] and WAY-100635 [11], which is evidence that there are significant distinctions in the structure of binding centers of the aforementioned receptor types. The search for and identification of specific structural features of buspirone analogs and determining their selectivity with respect to 5-HT1A receptors [8, 9] is important both for the synthesis of drugs producing selective therapeutic action and for the basic knowledge of ligand – receptor interactions. This work is aimed at the synthesis of phthalimidoalkylpiperazines with variable polymethylene spacer lengths and different aryl fragment structures, determination of their affinity to 5-HT1A serotonin and D2 dopamine receptors in rat brain, and a comparative study of the anxiolytic properties.