title: Electron-donating para-methoxy converts a benzamide-isoquinoline derivative into a highly Sigma-2 receptor selective ligand.
abstract: The sigma-2 (σ2) receptor has been suggested to be a promising target for pharmacological interventions to curb tumor progression. Development of σ2-specific ligands, however, has been hindered by lack of understanding of molecular determinants that underlie selective ligand-σ2 interactions. Here we have explored effects of electron donating and withdrawing groups on ligand selectivity for the σ2 versus σ1 receptor using new benzamide-isoquinoline derivatives. The electron-donating methoxy group increased but the electron-withdrawing nitro group decreased σ2 affinity. In particular, an extra methoxy added to the para-position (5e) of the benzamide phenyl ring of 5f dramatically improved (631 fold) the σ2 selectivity relative to the σ1 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 σ2-over-σ1 selectivity of new ligands.
authors: Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, 1300 University Ave., Madison, WI 53706, USA.
authors: Abdol R
authors: AR
authors: Hajipour
authors: Lian-Wang
authors: LW
authors: Guo
authors: Arindam
authors: A
authors: Pal
authors: Timur
authors: T
authors: Mavlyutov
authors: Arnold E
authors: AE
authors: Ruoho
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D004583:Electrons; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*
chemical_list: D001549:Benzamides; D007546:Isoquinolines; D008024:Ligands; D017480:Receptors, sigma; C106107:sigma-2 receptor; C037689:benzamide; C039109:isoquinoline