Lever John R, Gustafson Jennifer L, Xu Rong, Allmon Rachel L, Lever Susan Z
Department of Radiology, University of Missouri-Columbia, 65211, USA.
Synapse. 2006 May;59(6):350-8. doi: 10.1002/syn.20253.
SA4503, a potent sigma(1) receptor agonist, is reported as having 103-fold higher affinity for sigma(1) (IC(50) = 17.4 nM) than sigma(2) (IC(50) = 1,784 nM) sites in guinea pig brain membranes. Modest structural changes appear to have major effects on sigma(1)/sigma(2) selectivity. The fluoroethyl analog, FE-SA4503, is described as having high primary affinity for sigma(2) sites (IC(50) = 2.11 nM) and a weaker interaction with sigma(1) sites (IC(50) = 6.48 nM). SA4503 and FE-SA4503 have been radiolabeled for PET studies, and both bind selectively to sigma(1) 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 sigma(1) (K(i) = 4.6 nM) over sigma(2) (K(i) = 63.1 nM) sites in guinea pig brain homogenates. Further, FE-SA4503 exhibits the same 14-fold selectivity for sigma(1) (K(i) = 8.0 nM) over sigma(2) (K(i) = 113.2 nM) receptors. The main differences from previously reported values stem from sigma(2) affinity determinations. This protocol, displacement of [(3)H]DTG binding to sigma(2) sites using (+)-pentazocine (200 nM) to mask sigma(1) sites, was validated by the proper rank order of sigma(2) 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 sigma(1)/sigma(2) binding selectivity.
SA4503是一种强效的σ1受体激动剂，据报道，它对豚鼠脑膜中σ1位点（IC50 = 17.4 nM）的亲和力比对σ2位点（IC50 = 1784 nM）高103倍。适度的结构变化似乎对σ1/σ2选择性有重大影响。氟乙基类似物FE-SA4503被描述为对σ2位点具有高亲和力（IC50 = 2.11 nM），而与σ1位点的相互作用较弱（IC50 = 6.48 nM）。SA4503和FE-SA4503已被放射性标记用于PET研究，并且在体内动物和人脑中均选择性地结合到σ1受体。我们制备了SA4503和FE-SA4503作为放射性配体开发工作的参考化合物。在我们的实验中，SA4503对豚鼠脑匀浆中σ1位点（K(i) = 4.6 nM）的选择性比对σ2位点（K(i) = 63.1 nM）高14倍。此外，FE-SA4503对σ1受体（K(i) = 8.0 nM）的选择性比对σ2受体（K(i) = 113.2 nM）高14倍。与先前报道值的主要差异源于σ2亲和力的测定。该方案，即使用（+）-喷他佐辛（200 nM）掩盖σ1位点，通过一组其他配体显示的σ2抑制效力的正确等级顺序来验证[（3）H]DTG与σ2位点的结合位移：ifenprodil > 氟哌啶醇 > DTG >>（+）-喷他佐辛。我们的pK(i)值与其他人先前研究的值之间观察到稳健的皮尔逊相关性（r = 1.0，P = 0.002；斜率 = 0.97）。这些发现与该活性系列的构效关系以及可能从依赖于定义的σ1/σ2结合选择性的实验中得出的结论有关。
