Structural similitudes between cytotoxic antiestrogen-binding site (AEBS) ligands and cytotoxic sigma receptor ligands. Evidence for a relationship between cytotoxicity and affinity for AEBS or sigma-2 receptor but not for sigma-1 receptor

1-Benzyl-4-(N-2-pyrrotidinylethoxy)benzene (PBPE) is a cyto toxic derivativ e of the antitumoral drug tamoxifen. PBPE binds with high affinity and spec ificity to the microsomal antiestrogen-binding site (AEBS). PBPE, as well a s some other high-affinity AEBS ligands, shares structural features with hi gh-affinity and selective sigma receptor ligands in the N-(arylethyl)-N-alk yl-2-(1-pyrrolidinyl)ethylamine class, such as BD1008, which are cytotoxic against tumoral cells. Based on these structural and pharmacological simili tudes, we set out to examine whether AEBS and sigma receptors could be rela ted binding sites. We showed that BD1008 had a high affinity for AEBS. Howe ver, prototypical sigma receptor ligands were very low-affinity competitors on AEBS. Surprisingly, AEBS ligands displayed a high affinity for sigma-1 and sigma-2 receptor subtypes, showing that AEBS and sigma receptor-binding sites were not mutually exchangeable. Moreover, phenytoin, which is an all osteric modulator of sigma-1 receptor, was a competitive inhibitor of [H-3] tamoxifen on AEBS. These results suggest that the tamoxifen-binding site on AEBS and the sigma ligand-binding site on sigma receptors were not identic al but. related entities. We also showed here that the high-affinity and sp ecific AEBS ligands also bound sigma receptors with high affinity. Moreover , the compounds that were capable of displacing tamoxifen from AEBS were cy totoxic against tumoral cells but not against the AEBS-deficient cell line Rtx-6. These results confirm that AEBS and sigma receptors might belong to the same family of proteins, and that the tamoxifen-binding site might be i nvolved in the cytotoxicity of AEBS ligands and some classes of sigma compo unds. (C) 1999 Elsevier Science Inc.