5-Methoxytryptoline, a Competitive Endocoid Acting at [3H]Imipramine Recognition Sites in Human Platelets
| Autor: | Salomon Z. Langer, Hans Schoemaker, Alain Segonzac, T. Tateishi |
|---|---|
| Rok vydání: | 1985 |
| Předmět: |
Blood Platelets
Tryptamine Imipramine Serotonin Indoles Serotonin uptake Receptors Drug Allosteric regulation Binding Competitive Biochemistry Cellular and Molecular Neuroscience chemistry.chemical_compound Non-competitive inhibition medicine Humans Binding site Receptor Chemistry Desipramine Ligand (biochemistry) Tryptamines Receptors Neurotransmitter Carrier Proteins Carbolines medicine.drug |
| Zdroj: | Journal of Neurochemistry. 45:249-256 |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1111/j.1471-4159.1985.tb05501.x |
| Popis: | 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-hydroxy-tryptamine (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 IC70 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 μM. 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. These data are compatible with the hypothesis that 5-methoxytryptoline may be an endogenous modulator that interacts competitively with the imipramine receptor associated with the 5-HT uptake complex. |
| Databáze: | OpenAIRE |
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