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5‐Methoxytryptoline, a Competitive Endocoid Acting at [ 3 H]Imipramine Recognition Sites in Human Platelets
Author(s) -
Segonzac A.,
Schoemaker H.,
Tateishi T.,
Langer S. Z.
Publication year - 1985
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1985.tb05501.x
Subject(s) - imipramine , tryptamine , chemistry , platelet , ligand (biochemistry) , non competitive inhibition , biophysics , receptor , endogeny , binding site , membrane , biochemistry , pharmacology , medicine , biology , enzyme , alternative medicine , pathology
5‐Methoxytryptoline potently inhibits [ 3 H]‐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 [ 3 H]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 [ 3 H]imipramine binding in human platelets with a Hill slope for inhibition close to unity and IC 70 values of 3,265 and 3,475 n M , respectively. This inhibition is, however, not competitive because both 5‐HT and tryptamine significantly decrease the rate of [ 3 H]imipramine‐receptor dissociation. Although 5‐methoxytryptoline potently inhibits [ 3 H]imipramine binding (IC 50 = 44 n M ) in human platelets with a Hill slope of unity, it does not affect the receptor‐ligand dissociation rate of [ 3 H]imipramine even at concentrations up to 100 μ M . 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 K d of [ 3 H]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.