Phenothiazine, inhibition

Finally, the inhibitory effects of phenothiazines on the formation of Of by PMNs have been interpreted as evidence for the participation of calmodulin in the transmission of the signal from the surface of the cell to the oxidase. One action of phenothiazines is to inhibit the effects of the complex of calmodulin and Ca . The activity of the effector molecule, such as phosphodiesterase, which would normally be stimulated by the binary complex of Ca with calmodulin, is not stimulated in the presence of phenothiazines. Jones et al. have shown that in both intact PMNs and in membranous fragments of PMNs stimulated with opsonized zymosan, phenothiazines inhibit the formation of Of. The hierarchy of potency of the various pheno-... 

The phenothiazines inhibit dopaminergic receptors in the CNS, a property thought to account for their neuroleptic effect. In addition, phenothiazines inhibit muscarinic, a-adrenergic, histaminic, and serotonergic receptors, which accounts for many of their toxic or undesirable side effects. 

Some other inhibitors from the patent literature include hydroquinone [129], ionoP [130], and quinone [131]. Other inhibitors used to stabilize MMA include butylated hydroxy toluene (BHT), phenothiazine, methylene blue, hydroxy-diphenylamine and di-/jc/<3-napthol [132]. Several good reviews of inhibition and inhibitors have been written [133-136]. The mechanisms of inhibition are subtle and complicated. For example, it has been reported that highly purified benzo-quinone acts as a retarder rather than an inhibitor [137]. It has been proposed... 

Common inhibitors include stable radicals (Section 5.3.1), oxygen (5.3.2), certain monomers (5.3.3), phenols (5.3.4), quinones (5.3.5), phenothiazine (5.3.6), nitro and nitroso-compounds (5.3.7) and certain transition metal salts (5.3.8). Some inhibition constants (kjkp) are provided in Table 5.6. Absolute rate constants (kj) for the reactions of these species with simple carbon-centered radicals arc summarized in Tabic 5.7. 

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). 

Ford, J.M., Prozialeck, W.C. and Hait, W. N. (1989) Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug... 

In 1983, chlorpromazine (86) and related phenothiazines were reported to inhibit cRBL (5.6 and 9.6 /seminal vesicle CO and platelet 12-LO [226]. Heterocycles such as phenothi-... 

Recently, several series of tetracyclic analogues related to tenidap, represented by (158) (X = S, O, or CH2 R = aryl), have been reported to display a better balance of 5-LO and CO inhibition [386]. However, these compounds may also be considered as modified phenothiazine, phenoxazines, and acridines, and the enhanced 5-LO inhibition may be more closely related to that of other phenothiazines such as (88). 

Taniguchi, S., Suzuki, N., Masuda, M., et al. (2005) Inhibition of heparin-induced tan filament formation by phenothiazines, polyphenols, and porphyrins. J. Biol. Chem., 280, 7614-7623. 

Antagonists. Most of the so-called Hi-antihistamines also block other receptors, including M-cholinoceptors and D-receptors. Hi-antihistamines are used for the symptomatic relief of allergies (e.g., bamipine, chlorpheniramine, clemastine, dimethindene, mebhydroline pheniramine) as antiemetics (meclizine, dimenhydrinate, p. 330), as over-the-counter hypnotics (e.g., diphenhydramine, p. 222). Promethazine represents the transition to the neuroleptic phenothiazines (p. 236). Unwanted effects of most Hi-antihistamines are lassitude (impaired driving skills) and atropine-like reactions (e.g., dry mouth, constipation). At the usual therapeutic doses, astemizole, cetrizine, fexofenadine, and loratidine are practically devoid of sedative and anticholinergic effects. Hj-antihistamines (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers. 

The tricyclic antidepressants (e.g., desipramine and amitriptyline) and some phenothiazines block the sympathetic neuronal amine uptake system they thereby would also block the uptake of guanethidine and thus reduce its hypotensive effectiveness. Conversely, guanethidine competitively inhibits the uptake of drugs that are substrates for neuronal uptake, such as the indirectly acting adrenomimetics, or sympathomimetics (see Chapter 10). 

Drugs that inhibit platelet function (e.g., aspirin) or produce thrombocytopenia increase the risk of bleeding when heparin is administered. Oral anticoagulants and heparin produce synergistic effects. Many basic drugs precipitate in the presence of the highly acidic heparin (e.g., antihistamines, quinidine, quinine, phenothiazines, tetracycline, gentamicin, neomycin). 

Many of these drugs have effects that are not mediated by Hi-receptors (Table 38.2). The antimuscarinic activity of several first-generation Hj-blockers may account for their effectiveness in combating motion sickness and their limited ability to suppress parkinsonian symptoms. The phenothiazines have some capacity to block a-adrenoceptors, whereas cyproheptadine Periactin) is an antagonist at serotonin receptors. Diphenhydramine Benadryl), pyrilamine (Ryna), and promethazine Phen-ergan) are effective local anesthetics. Many second-generation antihistamines also have been found to inhibit the non-histamine-mediated release of various... 

Mechanism of Action A phenothiazine that acts as an antihistamine, antiemetic, and CNS-antipsychotiC typical hypnotic. As an antihistamine, inhibits histamine at histamine receptor sites. As an antiemetic, diminishes vestibular stimulation, depresses labyrinthine function, and acts on the chemoreceptor trigger zone. As a sedative-hypnotic, produces CNS depression by decreasing stimulation to the brainstem reticular formation. Therapeutic Effect Prevents allergic responses mediated by histamine, such as rhinitis, urticaria, and pruritus. Prevents and relieves nausea and vomiting. Pharmacokinetics ... 

The concept of abnormal proteins in CJD may provide insights useful for drug design. The pioneering (and Nobel Prize winning) work of Prusiner has enabled the preliminary identification of prototype agents as therapies for CJD. Preliminary work identified two classes of compounds with therapeutic potential polysulphated molecules and tricyclic molecules (e.g., phenothiazines, aminoacridines). These compounds bind to PrP and endeavor to inhibit the PrP to PrP cascade of conformational change. 

The contraction of the central ring in the classical tricyclic agents to a dihydroanthra-cene is compatible with antidepressant activity though the resulting compounds at first sight more closely resemble the antipsychotic phenothiazines. Most of this small group of drugs owe their antidepressant activities to the inhibition of the reuptake of norepinephrine. 

In contrast, acute alcohol use can inhibit metabolism of other drugs because of decreased enzyme activity or decreased liver blood flow. Phenothiazines, tricyclic antidepressants, and sedative-hypnotic drugs are the most important drugs that interact with alcohol by this pharmacokinetic mechanism. 

Phenothiazines are antipsychotic agents that can be used for their potent antiemetic and sedative properties (see Chapter 29). The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors. Sedative properties are due to their antihistamine activity. The agents most commonly used as antiemetics are prochlorperazine, promethazine, and thiethylperazine. 

Another action of phenothiazines is to compete with NADPH for the oxidase, an inference which was based on fulfillment of the criteria for competitive inhibition in double reciprocal plots of 1/[NADPH] vs. 1/rate of formation of O in the presence and absence of inhibitor It seems worth considering that all the effects of phenothiazines might be mediated through this effect and that the process of activation represents the presentation of substrate to the enzyme from which, in the resting state, the substrate is kept separate. 

---