title: 5-Methoxytryptoline, a competitive endocoid acting at [3H]imipramine recognition sites in human platelets.
abstract: 5-Methoxytryptoline potently inhibits [3H]imipramine binding to membranes from the cerebral cortex and platelets. Since 5-methoxytryptoline, which appears to occur endogenously with particularly high levels in the human pineal gland, also inhibits 5-hydroxytryptamine (5-HT, serotonin) uptake, it should be considered as a putative endogenous ligand modulating 5-HT transport. As the 5-HT transporter complex comprises the imipramine and the substrate recognition sites, which interact allosterically, it was essential to define the mechanism of inhibition of [3H]imipramine binding by 5-methoxytryptoline. Human platelets show an active and saturable uptake of 5-HT and tryptamine. The uptake of both substrates appears to be mediated by the same carrier and it is inhibited by 5-methoxytryptoline at submicromolar concentrations. 5-HT and tryptamine inhibit [3H]imipramine binding in human platelets with a Hill slope for inhibition close to unity and IC50 values of 3,265 and 3,475 nM, respectively. This inhibition is, however, not competitive because both 5-HT and tryptamine significantly decrease the rate of [3H]imipramine-receptor dissociation. Although 5-methoxytryptoline potently inhibits [3H]imipramine binding (IC50 = 44 nM) in human platelets with a Hill slope of unity, it does not affect the receptor-ligand dissociation rate of [3H]imipramine even at concentrations up to 100 microM. The present experiments show that 5-methoxytryptoline, in spite of its chemical similarity to the indoleamine transporter substrates, interacts with the imipramine receptor through a mechanism of competitive inhibition. This conclusion is supported by a selective effect of 5-methoxytryptoline on the Kd of [3H]imipramine binding.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.forename: A
authors.initials: A
authors.lastname: Segonzac
authors.forename: H
authors.initials: H
authors.lastname: Schoemaker
authors.forename: T
authors.initials: T
authors.lastname: Tateishi
authors.forename: S Z
authors.initials: SZ
authors.lastname: Langer
mesh_terms: D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology*; D002352:Carrier Proteins; D003891:Desipramine / Q000494:pharmacology; D006801:Humans; D007099:Imipramine / Q000097:blood*; D007211:Indoles / Q000494:pharmacology*; D011955:Receptors, Drug; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000097:blood; D014363:Tryptamines / Q000097:blood
chemical_list: D002243:Carbolines; D002352:Carrier Proteins; D007211:Indoles; D011955:Receptors, Drug; D017981:Receptors, Neurotransmitter; D014363:Tryptamines; C027775:imipramine receptor; C009762:5-hydroxytryptoline; C045647:5-methoxytryptoline; D012701:Serotonin; C030820:tryptamine; C009804:tryptoline; D007099:Imipramine; D003891:Desipramine