Thioxanthenes

Abstract: The aim of the present investigation was to illustrate the antibacterial effect of various phenothiazine and thioxanthene derivatives on mycobacteria in vitro. It was demonstrated that clopenthixol is about twice as potent as chlorpromazine (CPZ) and levomepromazine-maleate is about half as potent as CPZ, measured by the inhibitory effect on the growth of the mycobacterial strains. Measured in the same way the stereoisomeric compounds of flupenthixol are shown to be more potent than the stereo-isomeric compounds of clopenthixol and chlorprothixen. The two last-named compounds are equal in potency. The stereo-isomeric analogs of the thioxanthene derivatives are equal in antibacterial potency against the slow-growing mycobacteria. The mycobacterial strains investigated show no difference in sensitivity between the cis (Z)--and and trans (E)--compounds of the thioxanthenes. It seems particularly promising that also the more resistant mycobacteria other than Mycobacterium tuberculosis, e.g. M. avium and M. intracellulare, are sensitive in the concentration range investigated. Considered as a whole, these results might be a stimulus to investigate the antimicrobial effect of the thioxanthenes in vivo.

Abstract: In dopamine (DA) receptor binding tests two different receptor populations can be measured. By using 3H-haloperidol or 3H-spiroperidol as ligands D-2 receptors are detected. When the thioxanthene neuroleptics 3H-cis (Z)-flupenthixol or 3H-piflutixol are used as ligands D-1 receptors coupled to adenylate cyclase can be detected. In displacement experiments butyrophenones (haloperidol and spiroperidol) and diphenylbutylpiperidines (pimozide) interact with D-2 receptors only, whereas thioxanthenes (cis [Z]-flupenthixol, cis [Z]-piflutixol and cis [Z]-clopenthixol) have equal affinity for D-1 and D-2 receptors. A similar differentiation is also seen in behavioral studies. The methylphenidate antagonistic effect of butyrophenones and diphenylbutylpiperidines is dramatically attenuated by concomitant treatment with an anticholinergic agent or a GABA agonist. The effect of thioxanthenes is almost unchanged. When mice are treated for 12 days with neuroleptics, supersensitivity to methylphenidate is induced. The supersensitivity is reversed by thioxanthenes, whereas butyrophenones and diphenylbutylpiperidines have no effect at all. These differenes do not appear to be due to a change in the affinity for DA receptors because the ability of cis (Z)-flupenthixol, haloperidol, DA or apomorphine to displace 3H-piflutixol or 3H-spiroperidol is the same in supersensitive and control mice. The results clearly demonstrate that neuroleptics acting on both D-1 and D-2 receptors have a behavioral profile different from that of neuroleptics acting exclusively on D-2 receptors.

Abstract: Five acidic calix[4]arenes with carboxylic or sulfonic groups at either the upper or lower rim of the cavity and one resorc[4]arene were investigated to separate three thioxanthenes (flupentixol, clopenthixol, chlorprothixene) and a dibenz[b,e]oxepin derivative (doxepin) with cis-/trans-isomerism by nonaqueous capillary electrophoresis (NACE). Partial filling of the capillary with the UV-absorbing selectors led to a low detection limit and an advantageous signal-to-noise ratio (S/N). A sufficient electrophoretic mobility of the calixarenes towards the anode was necessary to outweigh the oppositely directed electroosmotic flow (EOF). This depended from the functional groups, the dissociation and the hydrodynamic radius of the cyclophanes. In contrast, the resorcinarene was useable only by addition of sodium dodecyl sulfate (SDS) because only the complex of the two selectors had an anodic apparent electrophoretic mobility. p-Sulfonyl-calix[4]arene (ss-a1) was the most capable selector for all E/Z-isomers with maximal alpha-values ranging from 1.056 for doxepin to 1.224 for chlorprothixene. This was due to the sufficient migration in reversed direction to the EOF even at low pH* values of 3.0. Otherwise, electrostatic as well as hydrophobic interactions with the positively charged isomers seem to contribute to a superior recognition. Increasing the concentration up to 15 mM ss-a1 and using acidic media (pH* 5.0) led to high separation efficiency. Changing the organic solvent provides a powerful tool to improve selectivity with N,N-dimethylformamide-methanol (DMF-MeOH)-mixtures for thioxanthenes. Further electrophoretic parameters were optimized, such as the concentration of the electrolytes, the addition of SDS, the kind of electrolytes and the voltage. Distinct differences in selectivities were found between the derivatives with thioxanthene and dibenzo[b,e]oxepin ring system, respectively. Further, the different basic side chain was responsible for the different selectivity at higher pH* values. In contrast, the substitution at position 2 of the thioxanthenes played a secondary role. Based on the studies of single parameters a method for a simultaneous separation of the four pairs of isomers within 13 min was developed.