Reevaluation of fenpropimorph as a sigma receptor ligand: Structure-affinity relationship studies at human sigma(1) receptors

Fenpropimorph (1) is considered a "super high-affinity" sigma(1) receptor ligand (K-i = 0.005 nM for guinea pig sigma(1) receptors). Here, we examine the binding of 1 and several of its deconstructed analogs at human sigma(1) (h sigma(1)) receptors. We monitored their subtype selectivity b...

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Bibliographic Details
Published inBioorganic & medicinal chemistry letters Vol. 27; no. 13; pp. 2912 - 2919
Main Authors Sguazzini, Elena, Schmidt, Hayden R., Iyer, Kavita A., Kruse, Andrew C., Dukat, Malgorzata
Format Journal Article
LanguageEnglish
Published OXFORD Elsevier 01.07.2017
Subjects
Chemistry
Chemistry, Medicinal
Chemistry, Organic
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Physical Sciences
Science & Technology
SAFiR
HINT analysis
Radioligand binding
3D Molecular modeling
IDENTIFICATION
BINDING
EXPRESSION
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Summary:Fenpropimorph (1) is considered a "super high-affinity" sigma(1) receptor ligand (K-i = 0.005 nM for guinea pig sigma(1) receptors). Here, we examine the binding of 1 and several of its deconstructed analogs at human sigma(1) (h sigma(1)) receptors. We monitored their subtype selectivity by determining the binding affinity at sigma(2) receptors. In addition, we validated an existing pharmacophore model at the molecular level by conducting 3D molecular modeling studies, using the crystal structure of h sigma(1) receptors, and Hydrophatic INTeractions (HINT) analysis. Our structure affinity relationship studies showed that 1 binds with lower affinity at h sigma(1) receptors (K-i = 17.3 nM) compared to guinea pig; moreover, we found that none of the fenpropimorph methyl groups is important for its binding at h sigma(1) receptors, nor is stereochemistry. For example, removal of all methyl groups as seen in 4 resulted in an almost 5-fold higher affinity at h sigma(1) receptors compared to 1 and 350-fold selectivity versus sigma(2) receptors. In addition, although the O atom of the morpholine ring does not contribute to affinity at h sigma(1) receptors (and might even detract from it), it plays role in subtype (sigma(1) versus sigma(2) receptor) selectivity. (C) 2017 Elsevier Ltd. All rights reserved.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.04.088