paroxetine, Paxil
[Evaluation of 3H-paroxetine as a radiopharmaceutical for lung function]

[Article in Japanese]

Hashimoto K, Goromaru T.

The potential of 3H-paroxetine as a radiotracer for in vivo study of the function in mouse lung was examined. A high accumulation of radioactivity in the mouse lung was observed after intravenous administration of 3H-paroxetine. However, the distributions of radioactivity in the mouse lung were not significantly decreased by treatment with paroxetine or other monoamine uptake inhibitors (6-nitroquipazine, desipramine and GBR 12909). It was found that the radioactivity in the mouse lung at 1 hr after intravenous administration of 3H-paroxetine was due to unmetabolized 3H-paroxetine from TLC and HPLC analyses. Furthermore, 3H-paroxetine exhibits both saturable and high affinity binding sites in mouse lung with a maximal number of binding sites (Bmax) of 303 fmoles/mg protein and a dissociation constant (Kd) of 92.2 pM. These results suggest that 3H-paroxetine would be a suitable radiopharmaceutical for in vivo study of the function of lung as a metabolic organ of serotonin.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2530375&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
A common binding site for tricyclic and nontricyclic 5-hydroxytryptamine uptake inhibitors at the substrate recognition site of the neuronal sodium-dependent 5-hydroxytryptamine transporter.

Graham D, Esnaud H, Habert E, Langer SZ.

Department of Biology, Synthelabo Recherche (L.E.R.S.), Paris, France.

An investigation of the site of interaction of a variety of tricyclic and nontricyclic 5-HT uptake inhibitors with the neuronal sodium-dependent 5-HT transporter was undertaken. The dissociation of [3H]paroxetine binding induced by indalpine (10 microM), SL 81.0385 (10 microM), fluoxetine (10 microM), citalopram (10 microM), paroxetine (0.15 microM), imipramine (10 microM) and 5-HT (50 microM) produced monophasic dissociation curves and gave t1/2 values of dissociation similar to that induced by dilution alone. In inhibition studies of [3H]paroxetine binding with citalopram, imipramine and 5-HT, increases in the concentration of [3H]radioligand used led to parallel rightward shifts of the inhibition curves with no diminution of the maximum degree of inhibition (Imax). "Schild-type" analyses of the data obtained from the inhibition curves with these 3 compounds gave slopes close to unity. In chemical modification studies, treatment of membrane fractions with N-ethylmaleimide led to a pronounded reduction in specific [3H]paroxetine binding. Preincubation of these membranes with SL 81.0385, fluoxetine, imipramine, tryptamine and 5-HT provided significant protection against this NEM-induced inactivation. The above findings are interpreted to provide evidence for a common or at least overlapping binding site for the tricyclic and nontricyclic 5-HT uptake inhibitors with the substrate recognition site of the neuronal sodium-dependent 5-HT transporter.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2532013&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Inhibition and dissociation of [3H]-paroxetine binding to human platelets.

Andersson A, Marcusson J.

Department of Geriatric Medicine, University of Umea Sweden.

Previous data on dissociation studies of [3H]-imipramine and [3H]-paroxetine binding to the human platelet 5-hydroxytryptamine (5-HT, serotonin) transporter have suggested that the binding is heterogeneous in nature and/or is subject to allosteric modifications through a separate low affinity site. The platelet 5-HT transporter is often used as a biological marker in psychiatric conditions. Therefore, it was of interest to further characterize the 5-HT uptake site by using [3H]-paroxetine. The 5-HT uptake inhibitors tested (citalopram, clomipramine, imipramine, norzimeldine and paroxetine) and 5-HT itself produced competitive inhibition patterns in saturation experiments, suggesting that these agents bind to the same site. In dissociation experiments in the presence of the 5-HT uptake inhibitors, the half-time values for dissociation were the same, whereas 5-HT slowed the dissociation. These data suggest that with the concentrations used of the 5-HT uptake inhibitors, they do not modify the 5-HT transporter. However, in the presence of 5-HT, the [3H]-paroxetine dissociation is decreased, suggesting an allosteric modification of the [3H]-paroxetine binding site.

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paroxetine, Paxil
The activity of 25 paroxetine/femoxetine structure variants in various reactions, assumed to be important for the effect of antidepressants.

Plenge P, Mellerup ET, Honore T, Honore PL.

Psychochemistry Institute, Rigshospitalet, Copenhagen, Denmark.

Structure-activity relationships for 25 structural variants around the 5-hydroxytryptamine (5-HT) uptake inhibitors paroxetine and femoxetine have been investigated. Three parameters related to the 5-HT system were investigated: (i) The inhibition of [3H]5-HT uptake into rat brain synaptosomes, (ii) the inhibition of [3H]paroxetine binding to rat neuronal membranes and (iii) the effect of the compounds on the affinity of [3H]imipramine for the human platelet membrane binding site, measured as the dissociation rate of the [3H]imipramine human platelet membrane binding site complex. A highly significant correlation was found for 5-HT uptake inhibition and inhibition of [3H]paroxetine binding for the different substances, indicating that the two parameters are closely connected. However the slope of the regression line was only 0.6 and not 1.0; this may indicate that [3H]paroxetine binding is necessary, but not sufficient for 5-HT uptake inhibition. No correlation was found between the inhibition of [3H]paroxetine binding and the affinity of the compounds for the [3H]imipramine binding site complex. The two binding sites are therefore probably situated on different parts of the 5-HT transport system, the [3H]paroxetine binding site being part of the 5-HT transport mechanism whereas the [3H]imipramine binding site may represent a site modulating the activity of, and affinity for, 5-HT in the 5-HT transport mechanism. Structure-activity relationships among the substances showed that stereochemical changes from (-)- to (+)-trans changed the activity towards both 5-HT uptake inhibition and [3H]paroxetine displacement for most of the (-)-/(+)-pairs. The substitution of -H with -F or -CH3 also affected the activity.(ABSTRACT TRUNCATED AT 250 WORDS)

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paroxetine, Paxil
Paroxetine, a selective 5-hydroxytryptamine uptake inhibitor with antidepressant properties, lacks amphetamine-like stimulus properties in an operant drug discrimination bioassay in rodents.

Goudie AJ, Dubicki W, Leathley M.

Psychology Department, Liverpool University, UK.

To evaluate whether the novel antidepressant paroxetine has any possible amphetamine-like actions, rats were trained to discriminate (+)-amphetamine sulphate in a standard two lever operant drug discrimination (DD) procedure using a fixed ratio 10 schedule of food reinforcement with a quantal, lever selection, index of the amphetamine stimulus. The 'training' dose of amphetamine was 1 mg kg-1, i.p. Rats trained with this dose of amphetamine (n = 15) learned the drug discrimination rapidly over 30 training sessions and discriminative performance in these animals was subsequently maintained at a high level of accuracy (90% correct) over a prolonged time. In tests in these trained animals, amphetamine itself and the antidepressant agents nomifensine and tranylcypromine all produced clear, unequivocal dose-related generalization to amphetamine with ED50s of 0.2, 0.5 and 1.6 mg kg-1 respectively (as determined by probit analyses). In tests with paroxetine hydrochloride it was established that, over the dose range 0.3 to 10 mg kg-1, no evidence was seen of generalization to the amphetamine stimulus. These data confirm earlier studies which suggested that some antidepressants may possess abuse potential because of their ability to induce amphetamine-like internal states. In contrast, paroxetine is devoid of such properties.

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paroxetine, Paxil
Characterization of [3H]paroxetine binding to rat cortical membranes.

Habert E, Graham D, Tahraoui L, Claustre Y, Langer SZ.

Paroxetine is a selective and potent inhibitor of 5-hydroxytryptamine uptake into serotonergic neurons. The specific binding of [3H]paroxetine to rat cortical membranes at 22 degrees C was examined in this study. Our results indicate the presence of a single saturable high affinity binding component for [3H]paroxetine. Scatchard analysis revealed a Kd of 0.15 +/- 0.01 nM, and a Bmax of 549 +/- 36 fmol/mg protein. The kinetically derived dissociation constant was 0.034 +/- 0.008 nM. [3H]Paroxetine binding was inhibited selectively by 5-HT uptake blockers, and a good correlation was demonstrated between the potency of various drugs to inhibit [3H]paroxetine binding and [3H]5-hydroxytryptamine uptake. Also, lesions performed with the neurotoxin, 5,7-dihydroxytryptamine resulted in a 94% decrease in endogenous 5-hydroxytryptamine levels and concomitantly, a 90% reduction in [3H]paroxetine binding when compared to sham controls. These results indicate that the binding site labelled by [3H]paroxetine is associated with the neuronal 5-hydroxytryptamine transporter complex.

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paroxetine, Paxil
Parkinson's disease: decreased density of 3H-imipramine and 3H-paroxetine binding sites in putamen.

Raisman R, Cash R, Agid Y.

The density of high-affinity 3H-imipramine and 3H-paroxetine binding sites (two serotonin-uptake blockers) was decreased in the putamen of parkinsonian patients. The correlation between serotonin levels and the number of 3H-imipramine and 3H-paroxetine binding sites suggests that they are located on serotoninergic nerve terminals and could be used to study serotoninergic innervation in the human brain. Since imipramine and paroxetine are powerful antidepressants, these results furthermore suggest that decreased serotoninergic transmission may be implicated in the pathophysiology of depression in Parkinson's disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2938025&dopt=Abstract paroxetine, Paxil, Paxil CR