Bitopic Sigma 1 Receptor Modulators to Shed Light on Molecular Mechanisms Underpinning Ligand Binding and Receptor Oligomerization

The
sigma 1 receptor (S1R) is an enigmatic ligand-operated chaperone
involved in many important biological processes, and its functions
are not fully understood yet. Herein, we developed a novel series
of bitopic S1R ligands as versatile tools to investigate binding processes,
allosteric modulation, and the oligomerization mechanism. These molecules
have been prepared in the enantiopure form and subjected to a preliminary
biological evaluation, while in silico investigations
helped to rationalize the results. Compound 7 emerged
as the first bitopic S1R ligand endowed with low nanomolar affinity
(Ki = 2.6 nM) reported thus far. Computational
analyses suggested that 7 may stabilize the open conformation
of the S1R by simultaneously binding the occluded primary binding
site and a peripheral site on the cytosol-exposed surface. These findings
pave the way to new S1R ligands with enhanced activity and/or selectivity,
which could also be used as probes for the identification of a potential
allosteric site.