SA4503, a potent σ1 receptor agonist, is reported as having 103-fold higher affinity for σ1 (IC50 = 17.4 nM) than σ2 (IC50 = 1784 nM) sites in guinea pig brain membranes. Modest structural changes appear to have major effects on σ1/σ2 selectivity. The fluoroethyl analog, FE-SA4503, is described as having high primary affinity for σ2 sites (IC50 = 2.11 nM) and a weaker interaction with σ1 sites (IC50 = 6.48 nM). SA4503 and FE-SA4503 have been radiolabeled for PET studies, and both bind selectively to σ1 receptors in animal and human brain in vivo. We prepared SA4503 and FE-SA4503 as reference compounds for radioligand development efforts. In our hands, SA4503 is 14-fold selective for σ1 (K i = 4.6 nM) over σ2 (Ki = 63.1 nM) sites in guinea pig brain homogenates. Further, FE-SA4503 exhibits the same 14-fold selectivity for σ1 (Ki = 8.0 nM) over σ2 (Ki = 113.2 nM) receptors. The main differences from previously reported values stem from σ2 affinity determinations. This protocol, displacement of [3H]DTG binding to σ2 sites using (+)-pentazocine (200 nM) to mask σ1 sites, was validated by the proper rank order of σ2 inhibitory potencies shown by a panel of additional ligands: ifenprodil > haloperidol > DTG ≫ (+)-pentazocine. Robust Pearson correlation (r = 1.0, P = 0.002; slope = 0.97) was observed for our pK i values against those from a prior study by others. The findings have bearing on structure-activity relationships for this active series, and on conclusions that might be drawn from experiments relying upon defined σ1/σ2 binding selectivity.
- Positron emission tomography (PET)
- σ receptor
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience