Phenothiazine Nucleus Research Articles

Study of phenothiazine- and chlorpromazine-iodine complexes.

In the solid state, phenothiazine (PH) complexes with iodine to yield a resistivity minimum of 350 Ω·cm at 2:3 stoichiometry. The chlorpromazine (CPZ):I2 system behaves likewise, the minimum resistivity is 420 Ω·cm. The ESR signal intensities also peak at this ratio. Conductimetric titrations in acetonitrile solution indicate a stoichiometry between 1:2 and 2:3 for the PH:I2 complex. CPZ·HCl produces a conductivity peak at 1:2, while freshly prepared free base CPZ complexes with I2 in a 1:1 ratio at room temperature. CPZ aged in solution or in the solid state yields a 2:3 complex at room temperature changing to 1:2 at 50°C with I2 in acetonitrile. Infrared spectra of these complexes are reported and discussed. Those of the CPZ:I2 complex resemble that of liquid or supercooled CPZ rather than that of solid CPZ. The CPZ:I2 as well as the CPZ·HCl:I2 complexes show a new band at about 1700 cm−1. Palladous chloride tests of the complexes were negative, indicating the absence of iodide ions. From the similarity of the PH:I2 and CPZ:I2 complexes in their electrical properties and in view of the fact that the stable form for both occurs for the 2:3 ratio it is likely that the main donor activity of CPZ resides in the phenothiazine nucleus and not in the side chain. However, there is evidence of at least three different complex species in the PH:I2 or CPZ:I2 systems. The I2 complexes of both PH and CPZ strongly resemble the high-temperature forms of their donor parents; thus it is not unlikely that self-complexing takes place in PH and in CPZ, especially at elevated temperature.

Inhibition of Na +K +-activated adenosine triphosphatase activity in rat brain by substituted phenothiazines

The effects of fifteen substituted phenothiazines and certain other drugs were studied on microsomal Na +K +-activated ATPase in rat brain to attempt to relate their central nervous system effects with their inhibition of enzyme activity. The mean control activity of the preparation was 14·4 ± 0·2 μmoles P i /mg protein/15 min at 37° in the presence of Na +, K +, and Mg ++; and 3·3 ± 0·1 in the presence of Mg ++ alone. Certain substitutions on the phenothiazine nucleus were noted to increase the inhibitory potency. At position 2 of the phenothiazine nucleus, a trifluoromethyl group was more potent than a chloro group which was in turn more potent than hydrogen. At position 10, a piperazine side chain was more inhibitory than an aliphatic amine substitution. The sulfoxide derivatives of promazine, chlorpromazine, and triflupromazine did not inhibit Na +K +-ATPase activity at concentrations as high as 5 × 10 −4 M. Compounds which failed to influence Na +K +-ATPase activity at concentrations used in the phenothiazine studies were pentylenetetrazol, d-amphetamine, strychnine, γ-aminobutyric acid, and pentobarbital. The evidence in this report suggests that, for substituted phenothiazines, there may be a correlation between inhibition of brain Na +K +-ATPase activity in vitro and certain central nervous system effects in vivo.

Hepatic Secretion and Urinary Excretion of Three S35-Labeled Phenothiazines in the Dog

The present studies indicate that in the dog chlorpromazine, prochlorperazine, and trifluoperazine are rapidly absorbed from the intestine and that there is a rapid hepatic clearance of the phenothiazines. The biliary and urinary excretions of these compounds are greatly affected by the side chain of the phenothiazine nucleus. The "methylpiperazinylpropyl" side chain (prochlorperazine and trifluoperazine) markedly increases the rate of biliary excretion and reduces the urinary excretion of the parent compounds and/or their metabolites compared with the excretion of chlorpromazine and/or its metabolites (dimethylaminopropyl side chain). Moreover, chlorpromazine and/or its metabolites excreted in bile are reabsorbed from the intestine, resulting in an entero-hepatic recirculation.

An electroencephalographic study of some structural aspects of D-amphetamine antagonism in phenothiazine and related compounds

Twenty-six phenothiazine and other related non-phenothiazine compounds were administered to rabbits in conjunction with d-amphetamine sulfate. The various pharmacological agents were evaluated according to their ability either to reverse amphetamine-induced EEG alerting or to maintain a state of EEG synchrony in the presence of amphetamine. Most of the compounds studies possessed some degree of sympatholytic activity in terms of these EEG measures of amphetamine antagonism. The compounds having either a dimethylamino group at the terminal of the side chain or, in the absence of a dimethylamino endgroup, a sulfur atom between the two benzene rings of the nucleus exhibited sympatholytic activity. Compounds which had a chemical structure containing a substitution at both the sulfur and dimethylamino terminal positions were found to be poor or ineffective antagonists of amphetamine. Demethylation of the N,N-dimethylamine side chain was also found to produced a reduction of sympatholytic activity. Changes of the substituent in the 2-position of the nucleus and substitutions for the nitrogen of the phenothiazine nucleus were found to be unimportant determinants of the EEG effects studied.

Quantitative colorimetric method and extraction procedure for determination of chlorpromazine in animal tissues

A procedure for quantitative analysis of chlorpromazine from biologic tissues based on oxidation of CPZ by ferric ion in the presence of concentrated sulfuric acid, and on its extraction into alkaline ether, is described. Cherry-red chromophore is read spectrophotometrically. Eighty to ninety percent recoveries of chlorpromazine, after its incubation with brain homogenates, could be obtained by means of this method. The procedure was specific for chlorpromazine and other 2-chlorophenothiazines possessing a side chain on the ring nitrogen; color was not present, or a different color was obtained, with changes in the phenothiazine nucleus and with substitutions for chlorine in position 2.

実験的錐体外路症候群に関する研究

1) In order to study the experimental Parkinsonism, some Phenothiazine-Derivatives, e. g. Chlorpromazine 30 mg/Kg., Perphenazine 15 mg/Kg.. Trifluoperazine 5 mg/Kg.. Fulphenazine 5 mg/Kg.. Thioproperazine 10 mg/Kg.; and Bulbocapnine 15 mg/Kg. which had been used for study of the experimental catatonia customally, were injected into the peritoneum of the Cb-strain of male mice and the Wister-strain of male rats. Above 90% of the rats and mice showed parkinsonism after the abministration of these drugs.2) The parkinsonian rats and mice showed sluggish movements, abnormal postures, catalepsia-like-syndroms e. g. passivity, negativism, fixation, rigidity of muscles, vegetative signs and tremor. Rigidity of muscles was objectively proved by application of the priciple of the Wartenberg's fixation of position test which was adopted to identify parkinsonism clinically and the principle of the Richter's grasp reflex and by appearence of the normal motor units at a strech reflex of the M. Gastrocunemius in the electromyography.3) As the preliminary experiment, three methods to assay the activity of ChE were each compared using brain homogenates. These were the manometric assay by Ammon's method, the electrometric assay using “glass electrode” PH-meter by the modified Michel's method and the spectrophotometric assay by the modified Takahashi Shibata's method. Among these assay, the electrometric assay was the most accurate method to detect the activity of ChE of the brain. Following studies were carried out using this electrometric assay.4) The ChE activity of the whole cerebrum of parkinsonian mice induced medicamentally was measured and compared with that of normals using the electrometric assay. All of the Phenothiazine-Derivatives inhibited the ChE activity of the whole cerebrum. But Bulbocapnine did not.5) The brain of the parkinsonian Wister strain of male rats was separated into two parts. One included the cortical area, the another included the basal ganglia. The ChE activity of both parts was measured by the electrometric assay. In the parkinsonian rats induced by Phenothiazine-Derivatives, the ChE activity of the cortical area was within normal limits but that of the basal gangliar area was remarkably inhibited. Bulbocapnine exaggerated the ChE activity in the cortical parts, while contrastedly inhibited the ChE activity in the basal ganglia.6) Referring to the correlation of the inhibitory effect and the structures of the Phenothiazine-Derivatives, CF3 base which was replaced with 3'-H on the phenothiazine nucleus, had a relatively higher inhibitory effect than the another. Piperazinyl base which attached to the side chain of the Phenothiazine nucleus, had also relatively higher imhibitory effects.7) The problems occured here were discussed. Especially the correlation between parkinsonism and the possible roles of the cholinergic system, regarding to the change of the behavior of animals and the inhibition of the ChE activity or the basal ganglia of the parkinsonian rats were discussed.

Studies on Antiarrhythmic Action of Phenothiazine Derivatives (III) : Relationship between Antiarrhythmic Action and the Chemical Structures, Side Effect and Clinical Results

Recently some observations concerning to the antiarrhythmic action of phenothiazine derivatives especially chlorpromazine are reported. The first observation of the antiarrhythmic activity of chlorpromazine was reported by Courvoisier (1953), Kawasaki has demonstrated a suppressive effect of this drug on ectopic excitation of heart muscle produced by experimental myocardial infarction and barium intoxication in dogs. In this paper the author attempts to find a relationship between antiarrhythmic potency and chemical structure of phenothiazine derivatives and to evaluate the clinical effectiveness of chlorpromazine alone or the combined therapy with procaine amide and quinidine on various types of arrhythmias. A) Screening Method The extrasystoles were evoked in adult healthy dogs each weighing about 10kg, by intravenous injection of thiopental sodium in a dose of 0.025kg and 2% barium chloride solution in a dose of 3 mg/kg respectively. These extrasystoles continued about 60 minutes. For screening of antiarrythmic activity, a drug to be tested is injected intravenously immediately after a definite provocation of experimental arrhythmia. A positive result represents a complets cessation of arrhythmia within one minute after injection of a test material. Twenty-three preparations of phenothiazine delivatives were tested by this method. B) Relationship between antiarrhythmic action and the chemical structures 1) Most potency group : 4695R.P. was the most potency one among the phenothiazine delivatives in this experiments (Table I). The minimum effective doses was 0.1mg/kg, about one tenth that of chlorpromazine. 2) Moderate potent group : Chlorpromazine, Promazine, Acepromazine, were classified in this group. Minimum effective doses were about 1mg/kg. 3) Less potent group : 7024 R. P. Trimeprazine, 4909 R. P. Chlorpromazine S oxide, . . . These pharmacons were classified in this group. Minimum effective doses were varying from 3mg/kg to 100mg/ kg. As shown in Table I, the substistution of R (10 position of phenothiazine nucleus) has a great influence on their antiarrhythmic potency. By increasing or decreasing the number of C atoms or substitution to isoaliphatic chain in dimethylamino propyl radical of R position of chlorpromazine, their potencies were significantly decreased.

Excretion Patterns of Phenothiazine-S35 Compounds in Rats: Effect of Change in Structure on Metabolism

The excretion patterns of five S35-labeled phenothiazines were compared in rats following the oral administration of pharmacologically active doses. Substitution in the 2 position in the phenothiazine ring did not have any apparent effect upon the S35 excretion pattern. Differences in the structure of the side chain did have an effect upon the mode of S35 excretion. The urinary S35 excretion decreased and the fecal S35 excretion correspondingly increased as the side-chain structure was changed from 3-dimethylaminopropyl to 3-dimethylamino-2-methylpropyl to 4-methyl-1-piperazinylpropyl. At a dosage level of 9.0mg. of free base/Kg. in rats, the urinary S35 excretion following the oral administration of compound II [2-chloro-10-(3-dimethylaminopropyl) phenothiazine-S35 hydrochloride] was twice as great as the urinary S35 excretion following the oral administration of compound III [10-[3- (4-methyl-1-piperazinyl)-propyl]-2-trifluoromethylphenothiazine-S35 dihydrochloride]. The former compound contained a chlorine atom in the 2 position of the phenothiazine nucleus, while the latter contained a trifluoromethyl grouping at this position. The increased dosage level (9.0mg. of free base/Kg.) did not appreciably change the S35 excretion pattern of compound IV [10-(3-dimethyl-amino-2-methylpropyl)phenothiazine-S35 tartrate] and compound V [10-(3-dimethylamino-2-methylpropyl)-2-trifluoromethylphenothiazine-S35 hydrochloride].

Relative effectiveness of phenothiazine tranquilizing drugs causing release of MSH.

SummaryNine phenothiazine ataraxic drugs were found to cause melanophore dispersion in the intact frog; one drug was shown to be ineffective. All drugs tested in hypophysectomized animals were without effect. The drugs, therefore, are effecting the release of MSH by direct action on the hypophysis or indirectly via brain centers. Minimal effective doses of the drugs were correlated with substitutions on the phenothiazine nucleus. A parallel with milligram potency for therapeutic control of psychiatric disorders is noted.

Ring Closure and Fungistatic Activity

The ability of the phenothiazines to act as fungistatic agents against certain dermatophytes in vitro has been reported previously (1, 2). These compounds were alike except for the components of the straight chain attached to the phenothia-zine nucleus. At present, there are no reports concerning the fungistatic activity of phenothiazines in which there occurs an alteration in the basic ring structure Itself. It was of interest, therefore, to explore this possibility by testing a series of compounds in which the middle ring had been opened at the number 10 position. At the same time, it was decided to extend the study of the closed-ring phenothiazine derivatives.

A new adjunct to analgesia and sedation in labor: Preliminary report of results with promazine hydrochloride by intravenous injection

ANALGESIA and sedation are acknowledged :e.quisite.s to the manageme~t of labor. Despite years of research and chmcal tnal, however, there 1s still no agreement as to the most suitable measures for the purpose. As yet, no method has been reported that will adequately fulfill all eight criteria for pain relief during parturition: ( l) no respiratory or cardiovascular depression in the infant; (2) no deleterious effect (a<s circulatory, respiratory, or central nervous system disturbance) in the mother; ( 3) adequate alleviation of emotional tension and obtundation of pain; ( 1) no interference with the normal mechanism of labor; ( 5) no incompatibility with accepted anesthetics or other agents required during· labor and delivery; (6) retention by the patient of sufficient command of her mental faculties to permit satisfactory response to instructions; ( 7) rapidity of action; ( 8) ease of administration. With the advent of the so-called ''tranquilizers,'' obstetricians looked with new hope for the long-awaited agent that would provide the desired neuromuscular relaxation, and that could be safely administered by vein for rapid and definite response. Attention was directed to the phenothiazine series in particular, because of the rcputed • 2 potentiating effect of the various compounds in the group on the commonly used hypnotics and analgesics. Chlorpromazine, which is obtained by addition of a dimethyl amino n-propyl group to the phenothiazine nucleus, and a chlorine atom in the second position (Fig. 1), is known to have a pronounced depressive action on the central nervous system, particularly the central autonomic functions. Reports of the performanee of ehlorpromazine in sedation and analgesia during labor are now numerous.:l-r Many of these reports have appeared in the European literature, and have been reviewed more extensively elsewhere. 8 The American literature on this subject has been well analyzed by Anz and Smith. These authors describe a diversity of experiences and express varying degrees of disappointment with the results obtained. J<'or intravenous use in labor, the compound has been avoided because of the risk of precipitous fall in blood pressure and other toxic side effects. We continued to search for improved modifications of phenothiazine, the parent compound, and were led to try promethazine, a substance with strong

Fatal agranulocytosis occurring during promazine (sparine) therapy.

Promazine (Sparine) is 10-(3-dimethylaminopropyl) phenothiazine hydrochloride, one of the newer ataraxic drugs recently introduced into clinical practice. It is chemically related to chlorpromazine, both compounds containing the phenothiazine nucleus. The structure of promazine is the structure of chlorpromazine minus the chlorine atom. Promazine has been used in the management of patients with acute mental disturbances 1 and at this stage is not recommended for patients with chronic conditions. Nevertheless, a clinical trial in such patients was planned. In March, 1956, it was decided to give a course of promazine therapy to 97 patients (50 female, 47 male), all with chronic conditions, who had been hospitalized for from 5 to 25 years. So far as is known, there has been no report in the literature of a case of agranulocytosis resulting from promazine therapy. In order to furnish the first known direct evidence of toxic effects of promazine on the bone

Liver function and hepatic complications in patients receiving chlorpromazine.

The use of chlorpromazine [Thorazine, 10-(γ-dimethylaminopropyl)-2-chlorophenothiazine hydrochloride] is occasionally complicated by the development of jaundice. In our series of over 800 patients treated with this drug, 5 such cases have occurred. Results of laboratory studies in these instances have consistently indicated an obstructive process within the biliary system. The complication has proved to be benign, the ensuing clinical courses being characterized by rapid resolution of symptoms and uneventful recovery. Though this side-reaction occurred only rarely and was apparently confined to the bile passages, we believed that the possibility of damage to the liver cells demanded further investigation. Of particular concern to us was the question of whether patients receiving the drug over relatively long periods of time sustained subclinical liver damage. The presence of the phenothiazine nucleus in chlorpromazine further suggested the need for this determination, since phenothiazine itself, in sufficiently high dosage, has been reported to produce liver disease.