Phenothiazine Compounds Research Articles

Studies in the heterocyclic series. XXI. A novel tetraaza‐analog of phenothiazine

AbstractAs a continuation of our search for new pharmaco‐active phenothiazine compounds, the synthesis of 1,4,6,8‐tetraazabenzo[b]phenothiazine ring system is described. Derivatives of this new heterocycle were prepared by converting 4,5‐diamino‐6‐hydroxypyrimidine to 4,5‐diaminopyrimidine‐6‐(1H)thione followed by the action of 2,3‐dichloroquinoxaline in refluxing DMF or DMAC. The reaction of mixed nitric and sulfuric acids with 9‐amino‐12‐chloro‐1,4,6,8‐tetraazabenzo[b]phenothiazine gave 9‐amino‐12‐chloro‐13‐nitro‐1,4,6,8‐tetraazabenzo[b]phenothiazine 5‐oxide in satisfactory yields. Diazotization of 9‐amino‐1,4,6,8‐tetraazabenzo‐[b]phenothiazine led to 1,4,6,8‐tetraazatriazolo[4,5,1‐kl]benzo[b]phenothiazine which is a new heterocyclic compound and the parent compound of this ring system. The mechanistic pathways to these compounds are also proposed.

Determination of promethazine and other phenothiazine compounds by liquid chromatography wih electrochemical detection.

Determination of promethazine and other phenothiazine compounds by liquid chromatography wih electrochemical detection.

STUDIES IN THE HETEROCYCLIC SERIES. XIV. THE CHEMISTRY AND BIOLOGICAL ACTIVITY OF NEW AZA- AND THIA-PHENOTHIAZINES, AND RELATED DIBENZOTHIAZEPINES

Abstract Owing to increasing demand for phenothiazine compounds both in medicine and industry, novel rings in these series have been prepared and evaluated. The benzene rings have been replaced with pyrrole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, thiazine and triazine rings or their combinations leading to twelve new polyaza- and thia-phenothiazines. Expansion of the central thiazine ring in these systems has also been carried out. This article therefore provides a survey of the chemistry and applications of new polyaza- and thia-phenothiazine systems and their related thiazepines and thiazocines.

Free radicals of phenothiazine and related compounds. III. Selective Chlorination of Phenothiazines with Copper(II) Chloride

AbstractThe preferential introduction of chlorine atoms in position 1 of the phenothiazine ring by means of Cu(II) chloride is described.

Skin melanin pigmentation in schizophrenia

Skin melanin concentrations were measured by reflectance spectrophotometry in 76 schizophrenic patients (untreated by phenothiazine compounds), 76 matched non-schizophrenic psychiatric control patients (untreated by psychotropic drugs), and 80 normal subjects. The schizophrenics did not differ in skin melanin content from normal subjects, but they generally has significantly lower levels of skin melanin than the control patients. This difference was explained in terms of hypovitaminosis (with resultant hyperpigmentation) in the controls, many of whom were suffering from conditions likely to have exposed them to self-neglect and poor nutrition for prolonged periods.

Modification of the response of rats to lethal levels of ozone by enzyme-inducing agents

Rats injected daily with 30 mg/kg p-aminobenzoic acid (PABA) and exposed on day 4 to 8 ppm of the oxidant air pollutant ozone have a mean survival of 395 min, while the mean survival of uninjected control rats is 210 min and that of rats receiving a single injection of 30 mg/kg PABA just prior to ozone exposure is 212 min. These findings suggest that the mechanism by which PABA protects against ozone-induced lethal pulmonary edema is through the induction of an enzyme system. Studies with known modifiers of microsomal mixed function oxidase systems revealed that phenobarbital resulted in a decrease in rat survival time while allylisopropylacetamide resulted in an increase in survival. The phenothiazine compound chlorpromazine also resulted in an increase mean survival time after exposure to ozone.

Effect of phenothiazine neuroleptic drugs and tricyclic antidepressants on phosphodiesterase activity in rat cerebral cortex.

The activity of phosphodiesterase (PDE) of rat cerebral cortex following the administration in vitro and in vivo of various concentrations of neuroleptic phenothiazine drugs and tricyclic antidepressive drugs has been investigated. It has been shown that PDE activity is inhibited by phenothiazine neuroleptic drugs (fluphenazine > trifluperazine > thioproperazine > chlorpromazine = thioridazine). Tricyclic antidepressants nortriptyline, chlorimipramine, protiptyline, imipramine and desipramine at a concentration of 10−3 M caused 60–80% inhibition of PDE activity. It has also been found that the investigated phenothiazine compounds inhibit the high affinity PDE activity more than the PDE activity of low affinity to the substrate. The results obtained suggest that the mechanism of the neuroleptic action of phenothiazine drugs is partially connected with their influence on cyclic 3′,5′-AMP metabolism.

Polarographic determination of phenothiazine and N-substituted compounds

Phenothiazine was nitrated and the structure of the compound formed was elucidated by U.V., I.R., N.M.R. and mass spectroscopy techniques. It has been proved that two nitro-groups were fixed on the ring. The d.c. and a.c. polarographic reductions showed that the two nitro-groups were reduced into aminogroups. The reduction proceeds in two waves, with a total of 12 electrons. N-substituted phenothiazine compounds were also investigated using the same technique.

A sensitive thin-layer chromatography technique for determining morphine in urine

A screening procedure is described for determining morphine and other narcotics in acid-hydrolyzed urine. A simple pH adjustment and extraction are followed by washing the extracting solvent with a phosphate buffer which effectively removes hydrolytic products that normally produce inferior chromatograms. Interfering substances are discussed, with special reference to methadone, nicotine, caffeine, and phenothiazine compounds.

Interference of phenothiazine compounds in the colorimetric determination of inorganic phosphate.

Abstract It has been shown that phenothiazine derivatives interfere with the colorimetric determination of inorganic phosphate by methods in which phosphomolybdic acid is one of the reaction components. Furthermore, it has been shown that PTZ derivatives form a complex with phosphomolybdic acid which can be detected by infrared spectrophotometry. Such finding indicates that, in experiments trying to show the effect of phenothiazine derivatives on enzymes in which the assay of inorganic phosphate is the parameter used in order to define the enzymic effect, it is necessary to plan the experiment carefully.

Further characterization of a reduced nicotinamide-adenine dinucleotide phosphate-dependent aldehyde reductase from bovine brain: Inhibition by phenothiazine derivatives

The catalytic activity of partially purified NADPH-linked aldehyde reductase (alcohol: NADP oxidoreductase, EC 1.1.1.2) from bovine brain was inhibited by certain phenothiazines. The inhibition was competitive with respect to either NADPH or aldehyde as substrate and was found to vary with the pH of the reaction mixture. At pH 7.4 the inhibitor constants ( K l values) for chlorpromazine, trifluoperazine, and thioridazine were 7.0 × 10 −4 M, 3.3 × 10 −4 M, and 8.0 × 10 −4 M respectively. Promethazine ( K l value of 45.8 × 10 −4 M) was approximately 10 times less effective than chlorpromazine in producing inhibition of enzyme activity. In addition, chlorpromazine sulfoxide did not inhibit the rate of aldehyde reduction at concentrations as high as 10 −3 M. When the K l values for the various phenothiazines were compared with the reported ability of these compounds to abolish the unconditioned avoidance response in rats, it was observed that compounds with the lowest K l values had the lowest ED 50 for abolition of this response. Studies of product inhibition of bovine brain aldehyde reductase showed that either NADP or p-nitrobenzylalcohol were competitive inhibitors with NADPH or aldehyde as the variable substrate. These observations, together with the nature of inhibition produced by the phenothiazine compounds, strongly indicate a random order of addition of substrates to the enzyme.

Determination of Phenothiazine Compounds in Biologic Specimens by UV Spectrophotometry

A UV spectrophotometric technique for specific determination of drugs that have the phenothiazine group as part of their molecular structure was developed. The method utilizes the oxidation capability of the cobalt (III) ion. The phenothiazines and their sulfoxide metabolites are oxidized to a product that is stable in a hexane-tertiary butanol mixture. No other group of alkaline-extractable compounds gives a UV-absorbing product by the conditions of the proposed method. The procedure is sensitive, and the spectra of the products are highly specific for the phenothiazine drugs. Analysis is linear over the concentration range of 0.5–50.0 mcg./ml. The distribution pattern of certain phenothiazine drugs in the rat is presented.

Phenothiazine derivatives and brain zinc. Turnover radioactive isotope study.

Normal topographic brain zinc localization and the influence of three phenothiazine tranquilizers (chlorpromazine, thioridazine, perphenazine) were studied in vitro and in vivo in eight brain regions of 80 mice and 80 rats, from one hour till 21 days after injection of 5 and 15 microcuries of zinc chloride Zn 65, respectively. Brains of untreated animals took up 0.11%, 0.24% (maximum), and 0.16% of dose per gram, one hour, 7 and 21 days, respectively, after injection. Each of the phenothiazine compounds increases the total brain zinc uptake in all animals, more in rats than in mice. Regional changes were detected in rat brains: the occipitoemporal cortex, thalamus, and hippocampus are more zincophilic, the thalamus especially under chlorpromazine and the hippocampus under perphenazine treatment.

Molecular Sizes of Phenothiazines taken upon the Adsorption from Aqueous Solution and upon the Permeation through Cellulose Membrane

Mechanisms of pharmacological actions of phenothiazines have been known to be more or less based on the membrane actions.As in vitro studies of the membrane action, there have been often discussed the area occupied by one molecule of each phenothiazine compound at an interface, which is also important in discussing the interaction with other drugs at the interface.The present study was attempted to obtain the area occupied by one molecule of phenothiazines upon the adsorption from aqueous solution and the cross-sectional area evaluated from Stokes' radius of the molecule upon the permeation through cellulose membrane, discussing the results in comparison with the existing data concerning the similar values obtained from surface activity, the maximal stabilization of erythrocyte membrane and the steric structure.

Microdetermination of N-substituted phenothiazine compounds by coulometric techniques.

A method has been developed for the coulometric microdetermination ofN-substituted Phenothiazine compounds with electrogenerated cerium(IV), bromine and manganese(III). Quantities of 0.2–3 mg are determined with an average error of less than ±1% relative.

Electron-donating properties of phenothiazine and related compounds.

Electron-donating properties of phenothiazine and related compounds.

ARE LARGE DOSES OF INTRAVENOUS BARBITURATES JUSTIFIED FOR USE AS PREMEDICATION IN LABOR?

Abstract In many obstetric centers, large doses of intravenous barbiturates are used as premedication in labor; the prime consideration being to insure that the patient is asleep and will not remember her labor. The actual sedative effect on the mother and the depressant effect on the newborn with this type of premedication was studied in a group of 203 parturients. The results showed that the patients were not well sedated in labor, and even when the dose of barbiturate was markedly reduced and a phenothiazine compound (propiomazine) added, there was little improvement in quality of sedation. Comparing Apgar scores and times of sustained respirations of the newborn infants with a comparable group whose mothers had been premedicated with a small dose of narcotic (meperidine) and phenothiazine (propiomazine) also revealed a much more marked depressant effect in the barbiturate group. The price for amnesia in the mother is paid by the depressed newborn infant.

Stramonium psychodelia

The psychodelic actions of anticholinergic drugs has been reviewed. The compound of reference is stramonium. A history of use as well as the toxicology have been discussed. The best method of treatment at present seems to be intravenous diazepam followed by oral doses of the same drug. Phenothiazine compounds are contraindicated.

Oxidation of phenothiazine and related compounds by iodine in dimethylsulfoxide solution

Oxidation of phenothiazine and related compounds by iodine in dimethylsulfoxide solution

Are large doses of intravenous barbiturates justified for use as premedication in labor?

In many obstetric centers, large doses of intravenous barbiturates are used as premedication in labor; the prime consideration being to insure that the patient is asleep and will not remember her labor. The actual sedative effect on the mother and the depressant effect on the newborn with this type of premedication was studied in a group of 203 parturients. The results showed that the patients were not well sedated in labor, and even when the dose of barbiturate was markedly reduced and a phenothiazine compound (propiomazine) added, there was little improvement in quality of sedation. Comparing Apgar scores and times of sustained respirations of the newborn infants with a comparable group whose mothers had been premedicated with a small dose of narcotic (meperidine) and phenothiazine (propiomazine) also revealed a much more marked depressant effect in the barbiturate group. The price for amnesia in the mother is paid by the depressed newborn infant.