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Background: Medicinal chemistry traditionally requires the identification of biologically active molecules by synthesizing and screening each purified substrate. Further progress in drug discovery then requires definition of the structure-activity, relationship of the lead compound. More recently, combinatorial chemistry has emerged as a way to examine structure-activity relationships by screening a large mixture of compounds synthesized in a predictably random manner, without the labor-intensive costs of molecular isolation and purification. We set out to use this approach to examine the structural requirements for peptide binding to serotonin and dopamine transporters.Results: We screened a tripeptide cassette library for serotonin and dopamine reuptake inhibition using cloned transporter assay systems. The method has afforded a number of tripeptide pharmacophores with inhibitory IC50 values ranging from 10 μM to < 1 μM in the dopamine and serotonin reuptake systems. The conformation of one of these tripeptides, N-acetyl-d-Trp-t-Phe-d-Lys-CONH2 (which inhibits serotonin uptake with an IC50 of 10 μM) was compared to that of the serotonin uptake inhibitor s-fluoxetine, and was shown to be more similar in conformation to fluoxetine than was an analogous tripeptide containing l-Lys (IC 50 > 50 μM).Conclusions: We have identified five tripeptides with inhibitory IC50 values of < 10 μM in the serotonin reuptake system. One tripeptide was predicted to have pharmacophore features similar to that of fluoxetine, a selective and potent non-peptide serotonin reuptake inhibitor. Our results suggest that tripeptides derived from combinatorial libraries will help to define the important structural elements of pharmacophores.

Aus dem Phenacetylchlorid (I) wird durch Umsetzung mit Aluminiumtrichlorid und anschliesendes Einleiten von Ethen (II) das β-Tetralon (III) hergestellt.