Phenothiazine derivatives, inhibition

ATP inhibits only 6-PGDH and not G-6-PDH (G10). As previously reported for other enzymes, phenothiazine derivatives inhibit both G-6-PDH and 6-PGDH competitive with NADP since NADP protects G-6-PDH depending on its concentration (C4). Neither inhibiting nor activating action has been observed in phenylbutazone treatment (F2). 

Various interesting biomedical applications of phenothiazines were investigated, such as the anti-inflammatory effects of fluphenazine and triflupro-mazine, the use of chloropromazine and trifluoperazine to determine the secondary and tertiary structure of haemoglobin and myoglobin, and the efficiency of the promethazine (+) enantiomer to inhibit the bone resorbing cells, which led to the development of new methods for the treatment of periodontitis and osteoporosis. Recently, it was shown that some phenothiazine derivatives inhibited the production of prions in cultured neuroblastoma cells, suggesting that these phenothiazines might be applied to treat CJD. 

The antimalarial drug quinacrine and some phenothiazine derivatives, acepro-mazine, chlorpromazine, and promazine, have been used for the treatment of prion diseases (Doh-ura et al., 2000 Korth et al., 2001 May et al., 2003). The molecular mechanism associated with the inhibition of PrPsc formation by quinacrine remains unknown. However, it is proposed that quinacrine binds with human prion protein at the Tyr-225, Tyr-226, and Gln-227 residues of helix 3 (Vogtherr et al., 2003) and provides neuroprotection. Quinacrine may also act as an antioxidant and reduce the toxicity of prP 6 (Turnbull et al., 2003). 

Recent studies on multidrug reversal in mouse lymphoma and MDR/COLO 320 cells have shown that phenothiazine derivatives, namely perphenazine (2) and prochlorperazine dimaleate (4), effectively inhibited rhodamine efflux [171]. Other phenothiazine derivatives such as promethazine (1), ox-omemazine (20), methotrimeprazine maleate (18), triflupromazine (11), and trimeprazine (17) differently modulated intracellular rhodamine accumulation in these resistant cells. The effect of some substitution in the phenothiazine ring was studied in mouse lymphoma cells expressing P-gp [172], The 3,7,8-trihydroxy- and 7,8-dihydroxychlorpromazine derivatives were effective P-gp inhibitors, whereas 7,8-diacetoxy-, 7,8-dimethoxy-, 7-semicarbazone-, and 5-oxo-chlorpromazine derivatives exerted only a moderate effect. 

Apart from causing very well known cardiotoxic effects, phenothiazine derivatives can accumulate in lung epithelial cell membranes and therefore cause severe respiratory disorders. In the study performed by Ito et al. [279] it was found that CPZ (9) inhibited transepithelial Cl transport, mainly due to two mechanisms influence on the beta-adrenergic receptor and inhibition of basolateral potassium channels. The authors of this study also suggested that the recorded effects could result from the electrostatic interactions between the drug molecules and negatively charged components of the inner leaflet of the plasma membrane. 

Molnar, Beladii, and Foldes [69] studied antimycobacterial activity of five phenothiazine derivatives including chlorpromazine, levomeprazine, promazine, promethazine, and diethazine. The growth of Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium butyricum was found to be inhibited by chlorpromazine at practically identical concentrations. The minimum inhibitory concentrations for Mycobacterium tuberculosis were chlorpromazine and levomeprazine 10 xg/ml diethazine and promethazine 20 xg/ml whilst chlorpromazine sulphoxide was ineffective even at 100 xg/ml. Chlorpromazine and promethazine exerted a measurable bactericidal activity on Mycobacterium tuberculosis at 50 xg/ml total destruction of the organism and loss of acid fastness in part of the cells were shown at 300 xg/ml. Preliminary studies in mouse experiments revealed that phenothiazine derivatives were ineffective. 

Biochemically Nonspecific Group. Organic phosphates and carbamates inhibit pseudocholinesterase and other esterases. Toxicity and enzymatic inhibitory power are augmented by phenothiazine derivatives but reduced by chemicals which are SER- and esterase-stimulating but not by carbon tetrachloride. 

More recently, in the 1980s and 1990s new series of fused phenothiazine derivatives, the benzo[a,b or c]phenothiazines (BPHTs), were synthesized [3, 21 and references therein] and have received a great deal of attention, mainly because of their potential applications and their important biomedical properties [12-24]. Indeed, some BPHTs are coloured compounds and have been applied as polycyclic dyes or pigments for synthetic polymers, and also in optical recording media ([21] and references therein). Moreover, certain benzo [a or c]phenothiazine derivatives are potential anti-helmintics, possess an antiviral activity, for example inhibiting the multiplication of encephalomyocarditis viruses in tissue cultures ([21,22], and refer-... 

Konya A, Andor A, Satorhelyi P, Nemeth K, Kurucz I (2006) Inhibition of the MDR1 transporter by new phenothiazine derivatives. Biochem Biophys Res Commun 346(1) 45-50... 

Phenothiazine derivatives depress the chemoreceptor trigger zone for emesis, and large doses also inhibit the vomiting center. It has been reported that thiethylperazine depresses both the chemoreceptor trigger zone and the vomiting center (see Figure 73). 

Chlorpromazine and other phenothiazine derivatives (perphenazine, prochlorperazine, thioridazine, and triflu-promazine) may cause agranulocytosis. The incidence of these side effects is higher among female and elderly patients whose bone marrow has lower proliferative potential. These agents inhibit DNA polymerase, thymidylate kinase, and the incorporation of 3H-thymidine into DNA. Because the phenothiazine-induced agranulocytosis is a toxic reaction, it may be prevented by carefully monitoring the status of peripheral blood. 

Table 2.8. Approximate effectiveness of some derivatives of phenothiazine in inhibiting oedema-production by 5-hydroxytryptamine (5-HT) histamine, dextran, egg-white and compound 48/80...

Of the other sedatives and tranquillizers, tetrabenazine and related compounds have properties similar to reserpine, including the ability to reduce the monoamine content of brain and phenothiazine derivatives with tranquillizing actions uncouple oxidative phosphorylation and inhibit ATPase activity to an extent roughly corresponding to their tranquillizing... 

Phenothiazine derivatives and related compounds oxidise rapidly if dissolved. This degradation can be inhibited by the addition of 0.5 % ascorbic acid. 

We have found that the ecto-ATPase is optimally stimulated by Mn at concentrations of 3 x 10" or below, but we have also observed some exceptions (for instance, in mouse neuroblastoma where 10 M Ca was most effective and Mn did not stimulate). Mn concentrations in excess of 3 x 10 M are inhibitory. The ecto-ATPase seems widely distributed in eukaryotic cells. There has been an earlier report that the enzyme was not present on the surface of intact neurons (CUMMINS HYDEN, 1962) but it certainly is present on the surface of intact neuroblastoma cells (TRAMS 6e LAUTER, 1974 STEFANOVIC et ad, 1976b), Conventional sulfhydryl compounds or inhibitors have little effect on the enzyme and ouabain is not inhibitory. We have found that ecto-ATPase of cultured CNS cells was inhibited by certain phenothiazine derivatives. Micromolar concentrations of thiazines and tricyclic antidepressants were inhibitory in rat leukocytes (MEDZIHRADSKY et, 1975). There has been one report that adipocyte membrane Mg ATPase was markedly stimulated by insulin and by Concanavalin A (JARRETT Sc SMITH, 1974). ... 

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