Albert A Manian

Cardiovascular effects of several imipramine analogs were investigated in the anesthetized mongrel dogs. Significant reduction in the cardiac output produced by lower doses (2.5 mg/kg, i.v.) of imipramine and 2-OH-DMI was not due to a depression of myocardial contractility. In contrast, 2-OH-imipramine (1.25 mg/kg) and DMI (2.5 mg/kg) significantly reduced contractility within 10 min after i.v. administration; however, significant decrease in the cardiac output did not occur until after ...

A series of chlorpromazine metabolites and derivatives have been assayed for their ability to compete with 3H-haloperidol binding to dopamine receptors in membranes of rat corpus striatum. 3-Hydroxylation of chlorpromazine doubles affinity for receptor sites, while 7-hydroxychlorpromazine has a potency similar to that of chlorpromazine itself. Other patterns of hydroxylation reduce affinity. Side chain demethylation lowers affinity for binding sites. Several metabolites which lack ...

Tissue slices were prepared from paired areas of the rat hypothalamus and brain stem. Exposure of the brain slices for 6 min to 5×10−5 M norepinephrine (NE) consistently resulted in a 3- to 5-fold increase in the level of adenosine 3′,5′monophosphate (cyclic AMP). Prochlorperazine and 7-hydroxychlorpromazine at 10−5 M antagonized the increase of the cyclic nucleotide elicited by NE in the hypothalamus and the brain stem (p<0.01), while 8-hydroxychlorpromazine and imipramine were ...

Incubated tissue slices from rat cerebral cortex and medial and lateral hypothalamus readily accumulated cyclic adenosine 3',5'-monophosphate (cyclic AMP) in response to added norepinephrine (NE). The monohydroxylated derivatives of chlorpromazine (CPZ), prochlorperazine, perphenazine, promazine and fluphenazine and respective parent compounds including promethazine and thiothixene were the most potent inhibitors of the stimulation of cyclic AMP by NE. For the most part, the NE-induced ...

Inhibition by phenothiazine derivatives was evaluated with respect to the catalytic component of adenylate cyclase prepared from either a high speed particulate fraction of rat cerebral cortex and hypothalamus or neuronal and glial-enriched fractions from rat and rabbit cerebral cortex. The dihydroxylated analogues of chlorpromazine, prochlorperazine, perphenazine and promazine along with the dioxo form of chlorpromazine were the most potent inhibitors of either basal activity or ...

Dopamine (DA) at 10−4M readily activated adenylate cyclase in homogenates of neuronal and glial-enriched fractions prepared from rat cerebral cortex, thalamus, striatum and the total homogenate from the striatum. Several derivatives of phenothiazines were tested for their ability to modify either the control component or the DA-sensitive receptor moiety of the enzyme. Dihydroxy analogues of chlorpromazine (CPZ), prochlorperazine, perphenazine. promazine and 7.8-dioxo-CPZ exhibited the ...

The relative muscarinic anticholinergic actions of phenothiazines and related drugs are thought to regulate the propensity of these agents to elicit extrapyramidal side effects, especially those resembling the symptoms of Parkinson's disease. Pimozide, which closely resembles the butyrophenones in its chemical structure and its potent and selective dopamine receptor blockade, differs from the butyrophenones in its relatively low incidence of extrapyramidal side effects. In assays of the ...

The antiprotozoal activity of chlorpromazine against the pathogenic protozoan Leishmania donovani, in both its amastigote and promastigote stages, was characterized. Chlorpromazine at concentrations greater than or equal to 3.12 micrograms/ml (9.8 X 10(-6) M) produced a significant reduction in viable promastigotes. The minimal protozoacidal concentration for promastigotes, defined as that concentration which produced greater than or equal to 90% reduction in viable parasites after 18 h, ...

Effects of chlorpromazine (CPZ) and three metabolites (3,7-dihydroxy-CPZ; 7,8-dihydroxy-CPZ; 7-hydroxy-CPZ) on behavioral performance of rats were tested by three methods: (a) continuous nondiscriminative lever-pressing shock-avoidance response without a warning signal; (b) discriminative pole-climbing shock avoidance and escape; (c) discriminative control of behavior by drug states. Both types of avoidance were much more impaired by CPZ than by the metabolites. The metabolite producing ...

Certain pharmacological responses in mice and rats were contrasted following acute and chronic administrations of chlordiazepoxide. In both species, studies were conducted after oral or intraperitoneal administration of drug. The tests used were (a) hexobarbital sleeping time, (b) hotplate analgesia, (c) maximal electroshock seizure, (d) spontaneous motor activity, (e) forced locomotor activity (rotarod) and (f) pit avoidance learning. Differences in drug response between acute and ...

Cyclic guanosine 3' ,5'-monophosphate(cyclic GMP) levels were increased in incubated tissue slices from rat cerebral cortex in response to added cholinomimetic agents (carbachol and choline chloride) and neuroleptic compounds (chlorpromazine, 8-hydroxychlorpromazine, 7-hydroxychlorpromazine methiodide, haloperidol, thioridazine, chlorpromazine sulfoxide and promethazine). Calcium ion was required for this effect. Moreover, selected agents namely, 7,8-dihydroxychlorpromazine, ...

Data are presented for thin-layer chromatographic behavior of chlorpromazine and thirty-five of its metabolites, as well as for the thin-layer chromatographic behavior of forty-two still unidentified metabolites found free or as glucuronides in plasma, erythrocytes, urine or feces. Tables are given on the frequency of occurrence of each compound in each source. The presence and identification of several new phenothiazine metabolites and their methoxylated analogs are reported.

An exploratory study consisting of physiochemical and animal experiments was undertaken with the objective of developing one or more metal-L-DOPA chelate systems for an improved transport of L-DOPA into the brain. This approach is based on a theoretical speculation that the pyridoxal-dependent decarboxylation of L-DOPA in the precerebral areas might be obviated by an appropriate metal chelation of the aminocarboxylate end of the L-DOPA molecule. Equilibium studies on the interactions of ...

Conditions have been established for the quantitative formation of radiolabeled derivatives of chlorpromazine, chlorpromazine sulfoxide and their demethylated analogs in plasma extracts.Tritiated N-acetyl derivatives are formed from the demethylated compounds and C14-quaternary amines from the tertiary amines by acetylation and methylation, respectively. These reactions are quantitative over a wide range of concentrations.The reactions may be performed sequentially when chloropromazine ...