Evidence for various tryptamines and related compounds acting as substrates of the platelet 5-hydroxytryptamine transporter

Summary The aim of the present study was to answer the question whether amines other than 5-hydroxytryptamine (5-HT) and tryptamine act as substrates of the platelet 5-HT transporter. To this end, a large number of tryptamines, 5-HT receptor agonists and phenethylamines (which had IC₅₀ values for ³H-5-HT uptake inhibition of 145–24500 nmol l^–1) was examined in rabbit platelets in order to determine their ability to induce an outward transport of ³H-5-HT Platelets (the MAO of which was blocked) from reserpine-pretreated animals were loaded with ³H-5-HT and then exposed for 5 min to various concentrations (ranging from 0.25 to 40 times the IC₅₀) of each compound. The concentration-effect curves for the drug-induced increase in ³H-5-HT efflux served to determine values of E_max (maximum increase in efflux expressed in % of the ³H-5-HT content of cells) and EC₅₀ (drug concentration producing E_max/2).For the 24 compounds studied here (which included the 5-HT uptake inhibitors imipramine, citalopram, fluoxetine and cocaine) a linear correlation between EC₅₀ and IC₅₀ (r = 0.975) and a mean ratio of EC₅₀/IC₅₀ of 2.4 was found. Most of the compounds [e.g., (±)8-hy-ydroxy-2-(N,N-dipropylamino)tetralin, S(+)-methyl-5-HT, 5-carboxamidotryptamine and 5-methoxytryptamine] gave rise to E_max values (15.8–32.5%) that exceeded that brought about by imipramine (6.6%), indicating that they act as substrates of the 5-HT transporter; the ³H-5-HT outward transport observed in response to these substances was abolished in the presence of imipramine. Others (e.g., 2-methyl-5-HT and 5-methylurapidil) produced Emax values (3.4–14.3%) not significantly different from that of imipramine and, therefore, can be classified either as poor substrates or as inhibitors of the 5-HT transporter.Hence, many tryptamines and 5-HT receptor agonists are substrates of the platelet 5-HT transporter. The property of being substrates gives them the latent capacity to bring about release of endogenous 5-HT and, as a result, to cause indirect 5-HT receptor-mediated effects.Abbreviations MAO monoamine oxidase - 5-HT 5-hydroxytryptamine - 2-M-5-HT 2-methyl-5-HT - N-M-5-HT N-methyl-5-HT - N,N-DM-5-HT N,N-dimethyl-5-HT - S(+)-M-5-HT S(+)-methyl-5-HT - 5-CT 5-carboxamidotryptamine - 5-M-tryptamine 5-methyltryptamine - 5-MO-tryptamine 5-methoxytryptamine - 7-M-tryptamine 7-methyltryptamine - N-M-tryptamine N-methyltryptamine - N,N-DM-tryptamine N,N-dimethyltryptamine - N,N-DM-5-MO-tryptamine N,N-dimethyl-5-methoxytryptamine - (±)8-OH-DPAT (±)8-hydroxy-2-2-(N,N-dipropylamino)tetralin - 5-M-urapidil 5-methyl-urapidilSend offprint requests to R. Wölfel at the above address