Cis-flupentixol

Detailed interaction studies have been performed with the neuroleptic drugs cis-and trans-flupentixol. These stereoisomers, like trifluoperazine, act as modifiers of multidrug resistance in tumor cell lines, in which it has been observed that the trans isomer is about three times as potent as the cis form. Surprisingly, it was found that, in the case of these two stereoisomers, the slope of the curve 1/T2 vs. lecithin concentration is different. The steeper slope for tram-flu perilixol suggests that it interacts about twice as strongly with lecithin as does cis-flupentixol (Figure 3.38) [133],... 

The steeper slope for tram-flupentixol suggests that it interacts about twice as strongly with lecithin as does c/s-flupentixol (Figure 11 -20) [47], [95].This indicates a stereospecific interaction of these catamphiphiles with phospholipids. The strength of interaction of the stereoisomers with the negatively charged BBPS is more extensive than with the neutral DPPC [91], and the chemical shifts of the HI signals were different for trans- and cis-flupentixol. 

Figure 11-21 Plots of proton l/7 2 slopes of trans-flupentixol vs l/T" slopes of cis-flupentixol in a presence of phosphatidylcholine (DPPC) and b phosphatidylserine (DPPS) lipid environment (reproduced from [96] with permission from Wiley-VCH, D-69451 Weinheim, Germany).

Figure 11-22 Conformation of a irarw-flupentkol and b cis- flupentixol as obtained from the conformational analysis after energy minimization and selected in accordance with the NMR experimental data (hydrogen atoms omitted) (reproduced from [95] with permission fi om Wiley-VCH, D-69451 Weinheim, Germany).

It has been demonstrated that cis- (76) and frarcs-flupentixol (75) (see Fig. 5) inhibited the photo affinity labeling of P-gp by substrate analogues [173] Binding of several MDR modulators, among them TFP (5), to P-gp was shown by means of fluorescence quenching of the MIANS probe [174] or P-gp tryptophan fluorescence [175]. CPZ (9) is likely a P-gp substrate, as was shown in studies of its transport in membrane vesicles obtained from multidrug-resistant CCRF-CEM cells [176], and therefore it was used as a competitive inhibitor of drug transport mediated by P-gp [177]. 

Jorgensen A, Andersen J, Bjomdal N, Dencker SJ, Lundin L, Malm U (1982) Serum concentrations of cis(z)-llupcntixol and prolactin in chronic schizophrenic patients treated with flupentixol and cis(z)-flupentixol decanoate. Psychopharmacology (Berl) 77(l) 58-65... 

Fig. 3.38 Relation between MDR-reversing activity (ratio, reversal of resistance against doxorubicin) of cis- and trans-flupentixol and their degree of interaction with phospholipid...

Detailed interaction studies have a been performed with the neuroleptic drugs cis- and trara-flupentixol. These stereoisomers also act like trifluoperazine as modifiers of multidrug resistance in tumor cell lines where it has been observed that the rra i-isomer is... 

Figure 11-20 Relation between MDR reversing activity (reversal of resistance against doxorubicin) by cis- and /ra s-flupentixol and the degree of interaction wdth phospholipid liposomes (slope of the plot of changes in l/T as a function of lecithin concentration) (reproduced from [95] with permission from Elsevier Science, Amsterdam, The Netherlands).

The largest difference was observed for the HI proton, indicating a reduction in electron density around this nucleus in the case of frons-flupentixol. To indicate the main feature in the behavior of the hydrogens of these stereoisomers when interacting with the phospholipid, the slopes of cis- were plotted versus the slopes of frara-flupentixol in the DPPC and BBPS interaction. The structure of flupentixol and numbering of the protons is given in formula 9. 

Figure 11-21 shows that HI has tiie lowest slope, HIO the highest and H9 is in the middle range between HI and HIO on both plots. These hydrogens correspond to that part of the molecule related directly to the stereoisomeric differences between cis- and trans-flupentixol. 

The coupling constants of H9 (7.3 Hz) and HIO (7.2 Hz) can be related to the preferred conformations of cis- and /ra s-flupentixol and were used as constraints to calculate with the PCMODEL program the conformations which best fit the experimental data (Figure 11-22). Experimental and computational results support the assumption that cis- and trans-flupentixol could interact in a stereodependent manner with both phospholipids [96]. 

The principal action of neuroleptic drugs appears to be the blockade of the dopamine receptor in brain, demonstrated on the mouse brain (Carlsson and Lundqvist, 1963 Seeman, 1977) and in the schizophrenic patient (Horn and Snyder, 1971). Confirmatory evidence is supplied by the neuroleptic drug, flupentixol, a close relative of chlorprothixene 12.111). The double bond, arising from the 9-position, permits geometrical isomerism. The clinical benefits of this drug are confined to the cis isomer, and this is the only one that blocks the dopamine receptor in vitro (Crow and Johnstone, 1977). Parkinson s disease is characterized by dopamine deficiency in the brain, and is treated by administering dopamine (p. 103). But schizophrenia is characterized by a deleterious accumulation of dopamine in the forebrain, and possibly elsewhere. 

Flupentixol and haloperidol (antipsychotics) were extracted fiom serum and eluted on a 40°C cyanopropyl column (A = 254 nm) using a 92/11/3 acetonitrile/ methanol/water (0.1 M ammonium acetate) with 50 pL of triethylamine added/L mobile phase [1510]. The haloperidol eluted between the cis- and rraws-flupentixol peaks at about 10 min. Calibration curves were constructed from 0.5 to 20 ng/mL. Detection limits were reported as 0.1 ng/m (S/N = 3). Interestingly, in addition to the above analytes, the chromatogram also showed benpetdiol, clozapine, levo-mepromazine, chlorprothixene, olanzapine, respirodone, fluphenazinesulfoxide, melperone, and perazine, all of which are at least partially resolved from one... 

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