Discovery of potent dual ligands for dopamine D4 and σ1 receptors

During our work on exploration of molecules with some piperidine-triazole scaffolds, we realized that our compounds display chemical similarity with some sigma, as well as dopaminergic receptor ligands. Here we show that this series of molecules has indeed strong affinity both for sigma 1 and dopamine D4 receptors. Moreover, they appear selective towards sigma 2, dopamine paralogues D1, D2, D3 and D5 receptors and hERG channel. Extensive molecular dynamics with our lead compound AVRM-13 were carried out on sigma 1, supporting agonist activity of the ligand. Unexpectedly, several observations suggested the existence of a cation binding domain, a probable regulatory site for calcium.

Automated summary

A series of compounds with piperidine-triazole scaffolds were found to have strong affinity for dopamine and sigma receptors, with selectivity towards specific receptors and channels. The lead compound showed agonist activity and suggested the presence of a calcium-binding regulatory site.