Aromatic linker variations in novel dopamine D 2 and D 3 receptor ligands

Dopamine D -like receptors, especially D and D receptor subtypes, are important targets of antipsychotic agents. Many of these antipsychotics share an aliphatic linker element between a protonable amine group and an acyl-like moiety. Here, we have modified this aliphatic linker into phenylmethyl and...

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Published in:Archiv der Pharmazie (Weinheim) 2024-08, Vol.357 (8), p.e2400071
Main Authors: Di Biase, Cristian, Leitzbach, Luisa, Frank, Annika, Zivkovic, Aleksandra, Stark, Holger
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Leitzbach, Luisa
Frank, Annika
Zivkovic, Aleksandra
Stark, Holger
description Dopamine D -like receptors, especially D and D receptor subtypes, are important targets of antipsychotic agents. Many of these antipsychotics share an aliphatic linker element between a protonable amine group and an acyl-like moiety. Here, we have modified this aliphatic linker into phenylmethyl and phenylethyl linkers substituted in different positions. The design, synthesis, and in vitro evaluation of 18 dopamine D and D receptor ligands were performed in this study. Using a radioligand displacement assay, all ligands were found to have modest nanomolar affinity to D R and D R. N-(4-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}phenyl)acetamide (6c) demonstrates the highest D R and D R affinity values (pK values of 7.83 [D R] and 8.04 [D R]), featuring a slight preference to D R. This derivative can be taken as a reference structure for the development of a new class of D R and D R ligands.
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title Aromatic linker variations in novel dopamine D 2 and D 3 receptor ligands
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