Tertiary amines related to brompheniramine: preferred conformations for N-oxygenation by the hog liver flavin-containing monooxygenase.

The metabolism of racemic, (D)- and (L)-brompheniramine, a widely used antihistamine, was studied with microsomes and with highly purified flavin-containing monooxygenase (FMO) from hog liver. In addition, a number of other similar tertiary amines were evaluated as substrates for FMO activity from hog liver and the kinetic constants obtained were compared with brompheniramine. Although some N-demethylation was observed, the major metabolite of brompheniramine and the other tertiary amines examined in hog liver microsomes was the metabolite containing an aliphatic nitrogen N-oxide. Brompheniramine was extensively N-oxygenated by the highly purified FMO from hog liver. N-Oxygenation of brompheniramine in both microsomes and with highly purified FMO from hog liver was enantioselective. The Km for N-oxygenation of (D)-brompheniramine was markedly lower than the Km for (L)-brompheniramine. (E)- and (Z)-zimeldine are less conformationally flexible model compounds of brompheniramine, and these compounds were also examined and were found to be stereoselectively N-oxygenated by the highly purified FMO from hog liver. The similarities and differences in Km and Vmax values were evaluated in terms of possible conformations of the substrates determined by SYBYL molecular mechanics calculations. Distance map data indicated that FMO preferentially accommodated selected conformations of tertiary amines. Thus, (D)-brompheniramine and (Z)-zimeldine presumably have the aliphatic tertiary amine nitrogen atom and aromatic ring center at a defined distance and geometry and were more efficiently N-oxygenated than their respective isomers.

Effects of antidepressant treatments on dopamine turnover in depressed patients.

Effects of five antidepressant treatments--clorgyline, desipramine hydrochloride, electroconvulsive treatment, lithium carbonate, and zimelidine hydrochloride--on urinary outputs of dopamine, dihydroxyphenylacetic acid, and homovanillic acid (HVA) were investigated in unipolar and bipolar depressed patients. Clorgyline and lithium carbonate, which stabilized mood in bipolar patients, reduced the urinary output of HVA and whole-body dopamine turnover. Electroconvulsive treatment and zimelidine were without major effects, whereas desipramine had variable effects on these indexes of dopamine metabolism. Three patients, two receiving desipramine and one receiving clorgyline, who had increased HVA output during the drug treatments, became severely agitated and delusional.

[Mechanism of the inhibiting effect of atypical antidepressants and psychostimulants on the synaptosomal uptake of monoamines]. / Mekhanizm ingibiruiushchego vliianiia atipichnykh antidepressantov i psikhostimuliatorov na sinaptosomal'nyi zakhvat monoaminov.

The effects of viloxazine and zimelidine on reverse monoamine neurotransmitter uptake by crude synaptosomal fraction of the rat brain were studied and compared to those of imipramine, amphetamine and cocaine. Imipramine noncompetitively inhibited the uptake of all the monoamines under study, with a greater specificity as regards serotonin. Viloxazine and zimelidine strongly inhibited the transport of noradrenaline, dopamine and serotonine, the transport of the latter being inhibited to a greater degree. Kinetic analysis showed the active centers of noradrenaline and dopamine carriers to be very much alike, those of catecholamine and serotonin carriers to be less alike. The data obtained made it possible to describe (at least partly) the structure of the active centers of monoamine carriers and to specify the action modes of antidepressants and psychostimulants.

[Effect of serotoninergic substances on escape behavior in acute stress situations]. / Vliianie serotoninergicheskikh veshchestv na povedenie izbavleniia v situatsii ostrogo stress-vozdeistviia.

The data are provided on the effect of some serotoninergic substances on the avoidance behavior under acute stress. 5-Hydroxytryptophan, zimelidine (low doses), pyrenepyron, ciproheptadine, trazodon (high doses), produced a noticeable positive action on the behavior pattern under study. Quipazin and zimelidine (high doses) provoked an increase in the number of affective manifestations and a rise of the latent avoidance time. Regardless of an appreciable fall in the number of affective manifestations, the powerful sedative effect of m-chlorphenylpiperazine led to an increase in the latent response periods. It was shown that substances that produced a direct or mediated activation effect on the serotoninergic system had an appreciable favourable influence on the avoidance behavior, which was a consequence of a decrease in the animals' emotional excitement. Combination of serotonin-blocking properties (action on S2-autoreceptors) and dopaminergic properties brought about optimal results, provided that pyrenepyron was applied.

Effects of serotonin on memory impairments produced by ethanol.

Subjects treated with low or high doses of ethanol demonstrated impaired memory, particularly in tests involving the recall of poorly learned information. Zimelidine, an inhibitor of serotonin reuptake, reversed this ethanol-induced impairment. The serotonin neurotransmitter system may mediate learning and memory in humans and may determine some of the effects of alcohol on higher mental functions.

[Effect of chronic use of antidepressants on the state of benzodiazepine receptors in the mouse brain]. / Vliianie khronicheskogo primeneniia antidepressantov na sostoianie benzodiazepinovykh retseptorov golovnogo mozga myshi.

A study was made of the effect of a two-week administration of chlorimipramine, zimelidine and a morpholine derivative on benzodiazepine receptors of the mouse brain. The animals which received antidepressants demonstrated a significant increase in the binding sites of 3H-flunitrazepam without any changes in the dissociation constant as compared to control. The data on the evoked aggressiveness and latency of tonic corasole convulsions in the antidepressant-treated animals support the functional importance of the discovered changes in benzodiazepine receptors.

A double-blind comparison of zimelidine and desipramine in endogenous depression.

Zimelidine, a specific 5HT uptake inhibitor (final dose 225 mg), and desipramine, mainly a noradrenaline uptake inhibitor (final dose 150 mg), were given in random order to 24 in- and out-patients fulfilling the Research Diagnostic Criteria for Major Depressive Disorder, definite or probable endogenous type, for a 3-week treatment period. Nonresponders were crossed over to the other drug for another 3 weeks. There was a nonsignificant trend towards more overall improvement on desipramine. Some patients in both groups showed very little change during 3 weeks, indicating a bimodal distribution of response to either drug. Several nonresponders improved markedly upon direct crossing over to the other drug. There were few and mild side effects on both drugs, with no significant difference between them. No significant correlation was found between improvement and plasma concentrations of zimelidine, norzimelidine, or desipramine, whereas a significant positive correlation was found between improvement and platelet serotonin uptake inhibition (measured in fresh platelets incubated in diluted plasma from the patients) in zimelidine-treated patients.

Electroconvulsive treatment and lithium carbonate. Their effects on norepinephrine metabolism in patients with primary, major depressions.

Effects of electroconvulsive treatment (ECT) and lithium carbonate on norepinephrine metabolism were investigated in eight patients with primary, major depressions. A series of 12 ECTs reduced urinary norepinephrine and normetanephrine output significantly, and showed a tendency to reduce urinary vanillylmandelic acid output as well as whole-body norepinephrine turnover. Treatment with lithium carbonate significantly reduced urinary norepinephrine, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, and vanillylmandelic acid output as well as whole-body norepinephrine turnover. These findings point to a common effect of antidepressant treatments since they are similar to results produced by administration of three other types of antidepressant drugs: clorgiline, a specific monoamine oxidase A inhibitor; desipramine, a relatively specific norepinephrine reuptake Inhibitor; and zimelidine, a relatively specific serotonin reuptake Inhibitor. These drugs reduce total production of norepinephrine and/or its major metabolites in depressed patients. Thus, five antidepressant treatments with different mechanisms of action have a common overall effect on the system.

Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors.

Fluoxetine and nine other antidepressant drugs which interact with brain receptors for neurotransmitters were studied in vitro using radioligand-binding techniques and transmitter-coupled adenylate cyclase assays. Tricyclic antidepressant drugs (desipramine, imipramine, clomipramine, amitriptyline and doxepin) had marked affinity for alpha-adrenergic, muscarinic cholinergic and histaminergic H1 receptors, and lesser affinity for serotonin and dopamine receptors. Mianserin was relatively similar to some of the tricyclic compounds, whereas trazodone had less affinity for most receptors except serotonin and alpha-adrenergic receptors. Fluoxetine had little affinity for any of these receptors, and the same was true for zimelidine and fluvoxamine, two other selective inhibitors of serotonin uptake. None of the compounds showed much affinity for beta-adrenergic receptors, opiate receptors, gamma-aminobutyric acid receptors, or benzodiazepine receptors. The present findings with fluoxetine are consistent with the virtual absence of anticholinergic or other side effects often observed with tricyclic antidepressant drugs in animal models or during the treatment of depressed patients.

Zimelidine: a placebo-controlled trial in depression.

Twenty-eight hospital inpatients with a primary major depressive disorder were treated with either zimelidine or placebo. Patients were matched for age, sex, and initial severity of depression and assigned double blind to the treatment regimen. An initial dosage of 150 mg/day was used for up to 6 weeks. Zimelidine was significantly more effective in alleviating the symptoms of depression than placebo, with 82% of zimelidine and 25% of placebo patients showing clinical improvement. There were few complaints of severe side effects in zimelidine-treated patients, and few effects on the cardiovascular system. Two zimelidine-treated patients were withdrawn for suspected drug-related adverse events. Zimelidine was a safe, effective antidepressant in this group of patients.

Inhibitors of serotonin and noradrenaline uptake in human plasma after withdrawal of zimelidine and clomipramine treatment.

Ten patients with endogenous depression, who had not taken any antidepressive drugs for 3 months, were treated with 100 mg b.i.d. zimelidine (five patients) or 75 mg b.i.d. clomipramine (five patients) for 5-10 weeks. Blood samples taken before and at various times after stopping the treatment were analysed for plasma concentrations of the drugs and their desmethylated metabolites, the uptake of 14C-serotonin in platelets incubated in platelet rich plasma, the concentration of serotonin in whole blood, and the inhibitory effect of the plasma on the accumulation of 14C-serotonin and 3H-noradrenaline in rat hypothalamic synaptosomes. It was found that these uptake measures were normalized within 1 to 2 weeks after zimelidine withdrawal, whereas the effects after clomipramine persisted for 3 to 4 weeks. Norzimelidine, the desmethylated metabolite of zimelidine, caused the effects after zimelidine treatment. Both clomipramine and its metabolite desmethylclomipramine were involved in uptake inhibition after clomipramine treatment. The mean pretreatment values of 14C-serotonin uptake in the platelets did not differ significant from an age and sex matched control group.l

Effects of acute doses of zimelidine on REM sleep in rats.

Sleep EEG (7 h) were obtained from 11 rats given 5, 10, and 20 mg/kg zimelidine, and a control dose of saline. Zimelidine significantly suppressed REM sleep, lengthened REM latency, and reduced total sleep time (TST) in a dose-dependent manner. Sleep latency was not affected except at the highest dose of zimelidine. Slow-wave sleep (SWS) was not affected at any dose. The results are discussed in terms of their implication for the use of zimelidine in the clinical treatment of depression.