Sigma receptors are small
membrane proteins implicated in a number of pathophysiological conditions, including
drug addiction,
psychosis, and
cancer; thus, small molecule inhibitors of
sigma receptors have been proposed as potential pharmacotherapeutics for these diseases. We previously discovered that endogenous monochain N-alkyl
sphingolipids, including d-
erythro-sphingosine,
sphinganine, and
N,N-dimethylsphingosine, bind to the
sigma-1 receptor at physiologically relevant concentrations [Ramachandran, S., et al. (2009) Eur. J. Pharmacol. 609, 19-26]. Here, we investigated several N-alkylamines of varying chain lengths as
sigma receptor ligands. Although the K(I) values for N-alkylamines were found to be in the micromolar range, when N-3-phenylpropyl and N-3-(4-nitrophenyl)propyl derivatives of butylamine (1a and 1b, respectively), heptylamine (2a and 2b, respectively),
dodecylamine (3a and 3b, respectively), and
octadecylamine (4a and 4b, respectively) were evaluated as
sigma receptor ligands, we found that these compounds exhibited nanomolar affinities with both sigma-1 and
sigma-2 receptors. A screen of high-affinity
ligands 2a, 2b, 3a, and 3b against a variety of other receptors and/or transporters confirmed these four compounds to be highly selective mixed sigma-1 and sigma-2
ligands. Additionally, in HEK-293 cells reconstituted with K(v)1.4
potassium channel and the
sigma-1 receptor, these derivatives were able to inhibit the outward current from the channel, consistent with
sigma receptor modulation. Finally, cytotoxicity assays showed that 2a, 2b, 3a, and 3b were highly potent against a number of
cancer cell lines, demonstrating their potential utility as mixed sigma-1 and
sigma-2 receptor anticancer agents.