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At least 523 records · Page 29Linked to original sources
PubMed1979

Pharmacological characterization of perifornical hypothalamic dopamine receptors mediating feeding inhibition in the rat.

Mapping studies with central drug injections in the hungry rat have identified the perifornical lateral hypothalamus as being uniquely sensitive to the feeding suppressive effects of exogenous dopamine, as well as anorexic drugs which release endogenous catecholamines. In the present study, the hypothalamic dopamine-receptive sites mediating this phenomenon were pharmacologically characterized. These sites, studied via direct drug injection into the perifornical hypothalamus of freely moving, brain-cannulated rats, were found to be most responsive to dopamine, in a dose-dependent manner, but were also activated by other catecholamine receptor stimulants, with the order of potency being dopamine greater than apomorphine = epinine greater than norepinephrine. Clinically effective neuroleptic compounds antagonized these dopamine-sensitive sites, apparently in a competitive and stereochemically specific manner. The relative potency of the neuroleptics and structurally related compounds was calculated to be haloperidol greater than fluphenazine greater than chlorpromazine greater than pimozide greater than promazine. The ineffective neuroleptic promethazine, the tricyclic antidepressants imipramine and desipramine, and the antagonists of alpha-adrenergic, beta-adrenergic, cholinergic, and serotonergic receptors, did not manifest the ability to reverse dopamine's action. These results thus reveal properties of these hypothalamic dopamine-sensitive, feeding inhibitory sites which match to a large extent the characteristics recently identified for dopamine receptors in the periphery and extrahypothalamic brain areas.

Adrenergic alpha-Antagonists↗
PubMed1983

Phototoxicity of phenothiazine derivatives. I. Inactivating and mutagenic effects on bacteriophage øX174.

Inactivation of øX174 bacteriophages as a function of the irradiation time in the near-UV and in the presence of triflupromazine (TFPZ), promazine (PZ), chlorpromazine (CPZ) or methoxypromazine (MTPZ) proceeds according to single hit kinetics. Acepromazine (ACPZ) has no significant activity. At low concentrations (0.1 mM) TFPZ and PZ are the most active compounds. Higher concentrations (up to 5 mM) result in a protective effect by these two compounds but cause increased inactivation rates in the case of MTPZ or CPZ. Photoinactivation mediated by TFPZ or CPZ increases the reversion frequency of a øXamber mutant. Neither MTPZ nor PZ sensitization induces mutagenesis. The effect of NaN3 on the phage inactivation rate varies depending upon both the sensitizer and the concentration of the quencher. Phage inactivation in an N2 atmosphere is measurable only in the presence of high concentrations of CPZ and MTPZ. The drugs do not show any selectivity for calf thymus DNA or bovine serum albumin, at least as measured by dialysis equilibrium experiments.

Azides↗
PubMed1983

Phototoxicity of phenothiazine derivatives. II. Photosensitized cross-linking of erythrocyte membrane proteins.

Irradiation in the presence of O2, with near-UV light of five promazine (PZ) derivatives added to erythrocyte ghost membranes, causes covalent cross-linking between proteins as revealed by a progressive decrease in the amounts of proteins separable by electrophoresis after denaturation. The induction of cross-links in the two spectrin subunits is a single-hit process as a function of the irradiation time; relatively the rate constants (in min-1) of the photoreactions were 0.060 with chlorpromazine (CPZ), 0.039 with methoxypromazine (MTPZ), 0.031 with PZ, 0.029 with triflupromazine (TFPZ) and 0.006 with acepromazine (ACPZ). A main photochemical intermediate implicated in the spectrin aggregation seems to be the cation radical of the PZ derivatives. Indeed, (i) the chemically generated cation radicals can induce the reaction in the dark; (ii) the photoaggregation is regularly reduced upon addition of increasing concentrations of NaN3; (iii) NaN3 similarly affects the amount of cross-links induced by the isolated cation radicals. Hydroxyl radicals are also involved in the photocross-linking when the reaction is initiated only by MTPZ and not by the other sensitizers. In the absence of oxygen during irradiation, PZ, MTPZ and ACPZ completely loose their cross-linking activities whereas CPZ and TFPZ remain as efficient as in the presence of oxygen.

Animals↗
PubMedDate not supplied

Development of radioimmunoassay for chlorpromazine.

Antiserum against chlorpromazine (CPZ) was produced in rabbits immunized with CPZ hapten conjugated to bovine serum albumin. The antiserum was used to develop a radioimmunoassay for CPZ. As little as 10 pg of CPZ can be detected with this radioimmunoassay. Major metabolites, CPZ sulfoxide, Nor1 -CPZ and Nor2 -CPZ are not bound significantly by the antibody unless the concentrations are very high. Although the antibody can bind 7-HO-CPZ, 8-HO-CPZ and promazine, the concentrations required to produce a 50% inhibition of 3H-CPZ-antibody binding are 5-10 times greater than CPZ. The plasma levels of CPZ and some minor metabolites in rats following administration of 10 mg/kg i.v. were determined by radioimmunoassay and showed a biphasic decay curve. Brain levels revealed that following i.v. administration CPZ traverses the blood-brain barrier rapidly and achieves peak concentration within 5 min. Plasma and brain levels can be detected for at least 24 hr.

Animals↗
PubMed1976

A noradren aline sensitive adenylate cyclase in the rat limbic forebrain: preparation, properties and the effects of agonists, adrenolytics and neuroleptic drugs.

A method for the preparation of a noradrenaline sensitive adenylate cyclase from homogenates of the rat 'limbic' forebrain is described using Krebs--Ringer as the homogenising medium. Some of its properties resemble those reported previously by other workers, using slices. Its response to agonists show that it has the characteristics of a beta1-receptor i.e. the potency of 1-isoprenaline exceeds that of 1-noradrenaline which exceeds that of 1-adrenaline. Structure--activity analysis of the response of the adenylate cyclase to a range of adrenergic agonists shows a strict requirement for a catechol moiety and a beta-hydroxyl group. The activation of the enzyme by 1-noradrenaline is sensitive to stereoselective inhibition by 1-propranolol. The effect of a number of neuroleptic drugs was examined. Promazine was the most effective agent tested in antagonising the stimulation produced by 50 muM 1-noradrenaline, whilst the potent dopamine receptor antagonist, alpha-flupenthixol was only weakly active. Furthermore, there was no stereoselectivity in the antagonism produced by alpha- and beta-siomers of flupenthixol. Pimozide was not found to be a potent antagonist. Thus the spectrum of antagonism produced by neuroleptic drugs was quite different from that seen in the dopamine sensitive adenylate cyclase of the rat corpus striatum.

Adenylyl Cyclase Inhibitors↗
PubMed1984

Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake.

Inhibitor constants (Ki's) for blocking uptake of [3H]norepinephrine, [3H]serotonin, and [3H]dopamine into synaptosomal preparations of rat brain were determined for 25 antidepressants and putative antidepressants, some neuroleptics, stimulants, antihistamines and other monoamines. With Ki's we could directly and definitively compare the relative potencies of a drug at the three processes. Eighteen or 72% of the antidepressants (including tertiary amine tricyclics) were more potent at blocking uptake of norepinephrine than at blocking uptake of serotonin. Considering all three biogenic amines, 17 antidepressants were selective for blocking [3H]norepinephrine uptake, one (bupropion) was selective although weak for blocking [3H]dopamine uptake, and the remainder were selective for blocking [3H]serotonin uptake. The neuroleptics chlorpromazine and promazine were relatively potent at blocking uptake of [3H]norepinephrine and some tricyclic antidepressants (notably, trimipramine and butriptyline) were very weak at blocking any biogenic amine uptake.

Animals↗
PubMed1981

The effect of substituted phenothiazines on the mutagenicity of benzo[a]pyrene.

The effect of phenothiazine and 11 of its derivatives on the mutagenicity of benzo[a]pyrene, as measured by the Ames test was investigated. Significant anti-mutagenic activity was detected for 10 phenothiazine derivatives, with the 2-chloro derivative being the most effective inhibitor tested and promazine the only phenothiazine drug tested which has no demonstrable inhibitory activity. It is considered that the anti-mutagenic activity and therefore potentially anticarcinogenic activity of these derivatives should be of interest to epidemiologists.

Benzopyrenes↗
PubMed1986

Affinity for the dopamine D2 receptor predicts neuroleptic potency in decreasing the speed of an internal clock.

For each of five neuroleptics (chlorpromazine, haloperidol, pimozide, promazine, and spiroperidol), the dose required to produce a rightward horizontal shift of 15-20% for psychophysical bisection functions that relate the percentage of long responses to signal duration was determined in rats for two different signal ranges (2-8 sec and 4-16 sec). Affinity for the dopamine D2 receptor (from in vitro studies) predicted neuroleptic potency in producing the criterion shift of the timing functions, whereas affinity for other aminergic receptors (D1, D3, the alpha-noradrenergic receptor, S1, and S2) did not. The conclusion is that dopamine D2 receptors play a major role in determining the rate of temporal integration for time estimation.

Animals↗
PubMed1981

The effect of phenothiazines and their metabolites on prostaglandin production by rat basophilic leukemia cells in culture.

Seven clinically important phenothiazine drugs (chlorpromazine, promazine, triflupromazine, thioridazine, fluphenazine, trifluoperazine and perphenazine) stimulated synthesis of PGE2 and PGF2alpha in RBL-1 cells in culture. Structural differences in the side chain at N10 had little effect on their activities. Some of the metabolites also were active, in keeping with the clinical observation that phenothiazines may have antipsychotic effects long after the parent compound has been eliminated from the circulation. Among the chlorpromazine metabolites, methoxy substituents on the phenothiazine nucleus did not strikingly affect stimulating activity. Monohydroxy derivatives were slightly more effective than the parent compound; there was little difference between hydroxy substitution at 7 or 8 position. The 7,8 dioxo, the N-oxido, the sulfoxide, and the 7-OH glucuronide derivatives were inactive.

Animals↗
PubMedDate not supplied

Degradation of met-enkephalin by extracts of various regions of the human brain: effects of antipsychotics and narcotics in vitro.

Antischizophrenic drugs, reduced in a concentration-dependent fashion enkephalin degradation by the soluble and particulate fractions of the human cerebral cortex and cerebellum. The order of potency is as follows: thioridazine greater than chlorpromazine greater than fluphenazine greater than haloperidol greater than or equal to promazine with IC50 of 50, 80, 120, 200-250 micro M, respectively. Kinetic studies revealed non-competitive and competitive inhibition by thioridazine and chlorpromizine, respectively. Narcotics, were weak inhibitors of enkephalin degradation. For dl-, d-, l-methadone and l-alpha-acetylmethadol, IC50 was about 500 micro M, and 1000 micro M for heroin and morphine. It is suggested that inhibition of the degradation of endogenous morphinomimetic peptides in the CNS may be a crucial factor governing the pharmacology of some neuroleptics and other psychoactive drugs. Enkephalin-hydrolyzing activity was ubiquitous and exhibited considerable regional differences in the normal human and in Huntington's chorea brains. The rate of enkephalin degradation is generally higher in the subcortical nuclei than in the cortex and cerebellum. The highest hydrolytic activity was found in the substantia nigra, anterior thalamus, septal area, globus pallidus and caudate nucleus, in this decreasing order.

Antipsychotic Agents↗
PubMed1992

Sensitive determination of phenothiazines in body fluids by gas chromatography with surface ionization detection.

Fourteen phenothiazine derivatives were tested for their detection by gas chromatography (GC) with surface ionization detection (SID). The sensitivity of GC-SID was highest with trimeprazine and levomepromazine, which contain aliphatic tertiary amino side chains, and lowest with thiethylperazine and thioproperazine, which contain sulphur residues. Chlorpromazine, trimeprazine and promazine showed excellent linearity between the SID response and the drug amount in the range 0.25-3.0 pmol on-column. Their detection limits were as low as ca. 5-10 pg (15-30 fmol) on-column (250-500 pg per ml of body fluid). A detailed procedure for isolation of phenothiazines from human whole blood and urine using Sep-Pak C18 cartridges, before the GC with SID, is also presented. The recoveries of the drugs (100 pmol), which were added to 1 ml of whole blood or urine, were more than 79%. The baselines remained steady as the column temperature was increased.

Chromatography, Gas↗
PubMed1983

A TLC fluorescence derivatization assay for chlorpromazine and its non-conjugated hepatic microsomal metabolites.

Procedures for the assay of chlorpromazine (CPZ) and its metabolites were compared. An improved assay, involving organic extraction, thin-layer chromatography and fluorescence derivatization, was developed. The compounds were extracted from microsomal protein suspensions into 15% n-propanol in dichloromethane by successive extractions at pH 2 and pH 12. CPZ and its mono- and di-desmethyl, 7-hydroxy, N-oxide, sulphoxide and N-oxide-sulphoxide metabolites were separated using TLC on silica gel developed with methanol-acetone-ammonia (50:50:1 v/v/v). The compounds were extracted from the TLC plate with chloroform-methanol (2:1 v/v) and subjected to oxidation with hydrogen peroxide. The highly fluorescent oxidized derivatives were identified as sulphoxides by their fluorescence characteristics. Amounts of derivatized CPZ and metabolites were measured using derivatized promazine as the internal standard.

Journal Article↗
PubMed1993

ELISA screening with GC-MS confirmation of the tranquilizer chlorprothixene administered in subtherapeutic doses to horses.

A commercially available generic promazine ELISA kit is available which shows cross-reactivity for the tranquilizer chlorprothixene (CPT). The ELISA test readily detects the presence of CPT or its metabolites in equine urine for up to 24 h after the i.v. and i.m. administration of sub-therapeutic doses (4.5 mg) to three horses. Maximum concentrations (CPT equivalents) are obtained 2 h after i.v. dosing. No distinct concentration peak values are observed after i.m. administration. Following solid-phase extraction, confirmation of CPT and its metabolites by electron impact mass spectrometry after sub-therapeutic administration is not successful. The use of chemical ionization mass spectrometry however revealed the presence of at least four metabolites including; chlorprothixene sulphoxide, hydroxylated chlorprothixene and hydroxylated chlorprothixene sulphoxide.

Animals↗
PubMed1989

Open channel block of NMDA receptor responses evoked by tricyclic antidepressants.

The action of desipramine (DMI) and promazine on the response of mouse hippocampal neurons to the excitatory amino acid N-methyl-D-aspartic acid (NMDA) was investigated using whole-cell and single-channel recording. DMI at 20-50 microM was a potent, selective antagonist of responses to NMDA but not kainate or quisqualate. At -60 mV, the Kd for DMI block of responses to NMDA was 10 microM. The potency of DMI as an NMDA antagonist was highly voltage-dependent and behaved as though the Kd increased e-fold per 36 mV depolarization, reflecting an increase in the dissociation rate constant. Prior block of NMDA receptors with Mg2+ prevented binding of DMI, suggesting an action in the open channel. Single-channel analysis showed a decrease in the open time and burst length distributions, consistent with binding of DMI to open channels. We suggest that the action of DMI on NMDA receptor channels is similar to that of MK-801 and does not reflect binding to other domains, such as the regulatory sites for Zn2+ and glycine.

Animals↗
PubMed1993

Thiols as potential UV radiation protectors: an in vitro study.

The following thiols were investigated with regard to their possible UV-radiation protective properties: captopril, cysteamine, ergothioneine, mesna, mercaptopropionylglycine, N-acetylcysteine, and penicillamine. As a measure for protection, the inhibition of in vitro irreversible photobinding of the labeled phototoxic drugs chlorpromazine (CPZ) and 8-methoxypsoralen (8-MOP) to protein and DNA was used. Besides photobinding to biomacromolecules, the photodegradation of CPZ and the formation of promazine (PZH) and hydroxypromazine (PZOH) were measured as well. Because of the H-atom and electron donating capacity of the thiols, the ratio [PZOH]/[PZH] was expected to be decreased and the photodegradation of CPZ was expected to be higher in the presence of thiols. Maximum inhibition of CPZ photobinding ranged for the different thiols between 21-100% (DNA) and 17-87% (human serum albumin). All thiols enhanced the photodegradation of CPZ (19-84%) and inhibited the ratio [PZOH]/[PZH] (90-97%). 8-MOP photobinding to human serum albumin was also clearly inhibited (75-96%), but remarkably less to DNA (2-41%). This study indicates that thiols are able to cope with a variety of reactive species. Scavenging of radicals, quenching of singlet molecular oxygen species and reaction with excited states seem to be essential mechanisms involved with this process.

Chlorpromazine↗
PubMed2006

Use of a fluorescent polarization based high throughput assay to identify new calmodulin ligands.

In order to develop a fluorescence polarization (FP) assay for calcium binding proteins, a fluorescent peptides based library of 1328 compounds has been synthesized. The use of this library has been validated by setting up a FP-high-throughput screening (FP-HTS) assay for calmodulin using the synthetic gene product (synCaM). With this assay, a set of 880 FDA approved compounds was screened. Besides the promazine class, we discovered two new classes of compounds that interact with calmodulin in a calcium dependent manner. One class has compounds with anti-histaminic/spasmolytic activities, and the other one are detergents with antibacterial activities.

Calcium-Binding Proteins↗
PubMed2004

Dissociation constants of phenothiazine drugs incorporated in phosphatidylcholine bilayer of small unilamellar vesicles as determined by carbon-13 nuclear magnetic resonance spectrometric titration.

The dissociation constants (pKms) of the phenothiazine drugs promazine, chlorpromazine, and triflupromazine, incorporated in the phosphatidylcholine (PC) bilayer of small unilamellar vesicles (SUV), were investigated by a 13C nuclear magnetic resonance (NMR) titration method employing their N-13CH3 (ionizable group) labelled derivatives. Use of the labelled drugs enabled direct observations of the ionization equilibrium of the N-dimethyl group. A second derivative spectrophotometric study proved that 95-98% of the phenothiazine species in the sample solutions (200 microM phenothiazine in the presence of 27 mM PC SUV) were incorporated into the PC bilayer, which simplified the calculation of pKm values by allowing that the phenothiazines in the aqueous phase could be neglected. The pKm values were calculated from the chemical shift dependence of the N-dimethyl 13C NMR signal on the pH value of sample solutions. The pKm values obtained were smaller than those measured in aqueous solutions by about one unit. The existence of cholesterol (30 mol%) in the PC bilayer showed little effect on the pKm values, suggesting that cholesterol in the bilayer does not largely affect the interfacial region where the N-dimethyl group of the incorporated phenothiazines is located. The results offered clear evidence for the pKm decrease and provided their precise values.

Carbon Isotopes↗
PubMed2004

Peroxidase catalysed formation of cytotoxic prooxidant phenothiazine free radicals at physiological pH.

The antipsychotic phenothiazines may have other therapeutic applications because of their ability to kill bacteria, plasmids and tumor cells. They are also known to undergo a peroxidase-catalysed oxidation to form cation radicals that are stable at acid pH, but are not detected at a neutral pH. The objective of this project was to determine whether phenothiazine cation radical metabolites could cause oxidative stress at a neutral pH resulting in cytotoxicity. At a neutral pH, catalytic amounts of phenothiazines were found to be oxidised by a peroxidase/H2O2 system and also caused ascorbate, GSH and NADH cooxidation. NADH and GSH co-oxidation was accompanied by oxygen uptake and was increased by the addition of catalytic amounts of superoxide dismutase, indicating that the superoxide radical was formed. The phenothazines were different from other peroxidase substrates in that the NADH, ascorbate or GSH cooxidation was faster at pH 6.0 than pH 7.4, thereby partly reflecting the cation radical stability. The order of catalytic effectiveness found was promazine > chlorpromazine > trifluoperazine. Peroxidase/H2O2 also markedly increased phenothiazine cytotoxicity towards isolated rat hepatocytes at nontoxic phenothiazine concentrations. At both pH 6.0 and 7.4, the same order of phenothiazine catalytic effectiveness was observed as seen in the co-oxidation experiments. Cytotoxicity to hepatocytes could be attributed to oxidative stress as most hepatocyte glutathione oxidation and lipid peroxidation preceded phenothiazine induced cytotoxicity and that cytotoxicity was prevented by the antioxidant butylated hydroxyanisole. This hepatocyte/peroxidase/H2O2 system could be a useful model for studying drug induced idiosyncratic hepatic injury enhanced by inflammation.

Animals↗