Reevaluation of fenpropimorph as a σ receptor ligand: Structure-affinity relationship studies at human σ receptors.

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