Sigma receptors (SRs), including SR1 and SR2 subtypes, have attracted increasing interest
in recent years due to their involvement in a wide range of activities, including the modulation
of opioid analgesia, neuroprotection, and potential anticancer activity. In this context, haloperidol
(HAL), a commonly used antipsychotic drug, also possesses SR activity and cytotoxic effects. Herein,
we describe the identification of novel SR ligands, obtained by a chemical hybridization approach.
There were endowed with pan-affinity for both SR subtypes and evaluated their potential anticancer
activity against SH-SY5Y and HUH-7 cancer cell lines. Through a chemical hybridization approach,
we identified novel compounds (4d, 4e, 4g, and 4j) with dual affinity for SR1 and SR2 receptors. These
compounds were subjected to cytotoxicity testing using a resazurin assay. The results revealed potent
cytotoxic effects against both cancer cell lines, with IC50 values comparable to HAL. Interestingly, the
cytotoxic potency of the novel compounds resembled that of the SR1 antagonist HAL rather than the
SR2 agonist siramesine (SRM), indicating the potential role of SR1 antagonism in their mechanism
of action. The further exploration of their structure-activity relationships and their evaluation in
additional cancer cell lines will elucidate their therapeutic potential and may pave the way for the
development of novel anticancer agents that target SRs.
