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Evidence for the existence of at least two different binding sites for 5HT-reuptake inhibitors within the 5HT-reuptake system from human platelets. 1988

E A Biessen, and J A Norder, and A S Horn, and G T Robillard
Department of Medicinal Chemistry, Subfaculty of Pharmacy, University of Groningen, The Netherlands.

Chemical modification procedures have been used to study the interaction of tricyclic and non-tricyclic 5HT-reuptake inhibitors with the [3H]imipramine binding site (IBS). N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) induced a pronounced loss in [3H]imipramine binding due to a reduction in Bmax. Preincubation with reuptake inhibitors and subsequent inactivation by EEDQ revealed that imipramine and 5HT prevented the EEDQ-induced inhibition, but citalopram and fluoxetine did not. Thiol modification studies demonstrated that reduction by dithiothreitol (DTT) enhanced the binding of [3H]imipramine by increasing the Bmax. The thioselective reagents 1,1-diazobis- (N,N-dimethylformamide) (diamide), phenyl-arsineoxide (PAO) and N-ethylmaleimide (NEM) attenuated the binding capacity by lowering the Bmax. PAO, a reversible thiol reagent, prevented NEM alkylation indicating that dithiols are involved in the NEM-induced inactivation. Binding of tricyclics or non-tricyclics prior to PAO inactivation revealed that tricyclics provide complete protection against thiol modification, while the non-tricyclics do not. The results support the hypothesis that the 5HT-reuptake system of human platelets possesses at least two distinguishable binding sites.

UI MeSH Term Description Entries
D007099 Imipramine The prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group. Imidobenzyle,Imizin,4,4'-Methylenebis(3-hydroxy-2-naphthoic acid)-3-(10,11-dihydro-5H-dibenzo(b,f)azepin-5-yl)-N,N-dimethyl-1-propanamine (1:2),Imipramine Hydrochloride,Imipramine Monohydrochloride,Imipramine Pamoate,Janimine,Melipramine,Norchlorimipramine,Pryleugan,Tofranil
D011804 Quinolines
D011955 Receptors, Drug Proteins that bind specific drugs with high affinity and trigger intracellular changes influencing the behavior of cells. Drug receptors are generally thought to be receptors for some endogenous substance not otherwise specified. Drug Receptors,Drug Receptor,Receptor, Drug
D001792 Blood Platelets Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. Platelets,Thrombocytes,Blood Platelet,Platelet,Platelet, Blood,Platelets, Blood,Thrombocyte
D002352 Carrier Proteins Proteins that bind or transport specific substances in the blood, within the cell, or across cell membranes. Binding Proteins,Carrier Protein,Transport Protein,Transport Proteins,Binding Protein,Protein, Carrier,Proteins, Carrier
D003545 Cysteine A thiol-containing non-essential amino acid that is oxidized to form CYSTINE. Cysteine Hydrochloride,Half-Cystine,L-Cysteine,Zinc Cysteinate,Half Cystine,L Cysteine
D004229 Dithiothreitol A reagent commonly used in biochemical studies as a protective agent to prevent the oxidation of SH (thiol) groups and for reducing disulphides to dithiols. Cleland Reagent,Cleland's Reagent,Sputolysin,Clelands Reagent,Reagent, Cleland,Reagent, Cleland's
D005033 Ethylmaleimide A sulfhydryl reagent that is widely used in experimental biochemical studies. N-Ethylmaleimide,N Ethylmaleimide
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001152 Arsenicals Inorganic or organic compounds that contain arsenic. Arsenic Compounds,Compounds, Arsenic

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