Tentative correlation between the electrochemical oxidation of neuroleptics and their pharmacological properties

Abstract

A number of drugs are largely metabolized after oral administration, especially by redox processes. Among the neuroleptics. loxapine. clotiapine and clozapine. which are sevenmembered tricyclic molé cules with a piperazine sidechain. are known to be extensively metabolized by oxidation. An electrochemical study of thèse compounds was initiated in order to détermine their in vitro redox properties and to elucidate their oxidation mechanisms. The measurements were carried out in aqueous and nonaqueous média using voltammetric, cyclic voltammetric, coulometric. exhaustive electrolysis and thinlayer spectroelectrochemical techniques. The oxidation mechanisms, which differ essentially depending on the pH of the solution, are suggested. In view of thèse results, various similarities have been detected between the in vitro oxidation processes and the pharmacological behaviour reported in the literature. For example, the importance of the piperazine sidechain has been pointed out: oxidation no longer occurs if this sidechain is protonated; similarly, binding to the receptor is prevented if the lone électron pair of the tertiary atom is occupied. Nucleophilic additions have aiso been observed in nonaqueous média and the compounds have been identified using classical spectroscopic techniques. If the oxidation mechanism is identical on the piperazine chain for the three compounds. the process is somewhat différent when it occurs on the tricyclic ring. Loxapine and clotiapine exhibit différent behaviour from clozapine, in their electrochemical as well as in their pharmacological properties.

Electrochemical and spectrophotometric characterisation of protein kinase inhibitor and anticancer drug danusertib

“…6A and B, it is proposed that the oxidation involves the piperazine moiety. The redox behaviour of piperazine containing compounds has been previously reported [22][23][24][25][26]. Considering that in acid media piperazine moiety is protonated (pK a1 ~ 7 and pK a2 ~ 3), the electrochemical oxidation of danusertib at peak 3 a occurs with the transfer of two electrons and two protons from the nitrogen atom in the proximity of the methyl group leading to the formation of iminium cation, Scheme 2C, which is hydrolysed forming an amine derivative and formaldehyde [26].…”

Electrooxidation Potential as a Tool in the Early Screening for New Safer Clozapine-like Analogues

“…It is worthwhile to point out that our previous investigations have shown a possible relationship between the electrooxidation of dibenzazepine analogues and their pharmacological properties . Voltammetric data have permitted to show that the electrooxidation occurred on the tricyclic ring and that the lone pair of electrons on the nitrogen (diazepine nucleus) is more readily available than the electron pairs of sulfur (thiazepine moiety) or oxygen (oxazepine moiety) .…”

“…It is worthwhile to point out that our previous investigations have shown a possible relationship between the electrooxidation of dibenzazepine analogues and their pharmacological properties. 44 Voltammetric data have permitted to show that the electrooxidation occurred on the tricyclic ring and that the lone pair of electrons on the nitrogen (diazepine nucleus) is more readily available than the electron pairs of sulfur (thiazepine moiety) or oxygen (oxazepine moiety). 45 In the present work, although the detailed mechanism by which the electrooxidation of the investigated drugs occurs is currently unknown, the electrooxidation potential along with all the studied parameters can be regarded as valuable data in developing new tricyclic analogues with increased safety.…”

Investigation of the crystal structure and electrochemical properties of catena-poly[[chlorido(piperazin-1-ium–κN))cadmium(II)]-di-μ-chlorido]monohydrate

“…In particular, d 10 metal complexes have attracted much interest in recent years, not only because of their interesting structures but also because of their photoluminescence properties [12,13]. Although there have been several reports on the electrochemical behavior of piperazine molecules [14][15][16][17], study of their anodic oxidation in a coordinated polymer has not been reported. In this paper we report the preparation, crystal structure, IR spectroscopy, thermal stability, and the luminescence and electrochemical properties of a novel cadmium coordination polymer [Cd(pipH)(Cl)(l-Cl) 2 ] n ÁnH 2 O.…”