Fenpropimorph (1) is considered a "super high-affinity" σ1 receptor ligand (Ki=0.005nM for guinea pig σ1 receptors). Here, we examine the binding of 1 and several of its deconstructed analogs at human σ1 (hσ1) receptors. We monitored their subtype selectivity by determining the binding affinity at σ2 receptors. In addition, we validated an existing pharmacophore model at the molecular level by conducting 3D molecular modeling studies, using the crystal structure of hσ1 receptors, and Hydrophatic INTeractions (HINT) analysis. Our structure affinity relationship studies showed that 1 binds with lower affinity at hσ1 receptors (Ki=17.3nM) compared to guinea pig; moreover, we found that none of the fenpropimorph methyl groups is important for its binding at hσ1 receptors, nor is stereochemistry. For example, removal of all methyl groups as seen in 4 resulted in an almost 5-fold higher affinity at hσ1 receptors compared to 1 and 350-fold selectivity versus σ2 receptors. In addition, although the O atom of the morpholine ring does not contribute to affinity at hσ1 receptors (and might even detract from it), it plays role in subtype (σ1 versus σ2 receptor) selectivity.
Keywords: 3D Molecular modeling; HINT analysis; Radioligand binding; SAFiR.
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