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.
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.
Graham
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Department of Biology, Synthélabo Recherche (L.E.R.S.), Paris, France.
Esnaud
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Habert
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Langer
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D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005033:Ethylmaleimide / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000378:metabolism; D017374:Paroxetine; D010880:Piperidines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism*; D012964:Sodium / Q000494:pharmacology*
D000929:Antidepressive Agents, Tricyclic; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D005473:Fluoxetine; D015283:Citalopram; D012701:Serotonin; D017374:Paroxetine; D012964:Sodium; D005033:Ethylmaleimide; D007099:Imipramine; C018181:indalpine