Electron-donating para-methoxy converts a benzamide-isoquinoline derivative into a highly Sigma-2 receptor selective ligand

The sigma-2 (sigma 2) receptor has been suggested to be a promising target for pharmacological interventions to curb tumor progression. Development of sigma 2-specific ligands, however, has been hindered by lack of understanding of molecular determinants that underlie selective ligand-sigma 2 interactions. Here we have explored effects of electron donating and withdrawing groups on ligand selectivity for the sigma 2 versus sigma 1 receptor using new benzamide-isoquinoline derivatives. The electron-donating methoxy group increased but the electron-withdrawing nitro group decreased sigma 2 affinity. In particular, an extra methoxy added to the para-position (5e) of the benzamide phenyl ring of 5f dramatically improved (631 fold) the sigma 2 selectivity relative to the sigma 1 receptor. This para-position provided a sensitive site for effective manipulation of the sigma receptor subtype selectivity using either the methoxy or nitro substituent. Our study provides a useful guide for further improving the sigma 2-over-sigma 1 selectivity of new ligands. (C) 2011 Elsevier Ltd. All rights reserved.