GRIND-derived pharmacophore model for a series of α-tropanyl derivative ligands of the sigma-2 receptor^*

Abstract

A pharmacophore model for the sigma-2 receptor was derived using GRIND (GRid INdependent Descriptors) descriptors arising from a 3D-level procedure whose main prerogative is that it does not require ligand alignment. PLS models for sigma-2 affinity (sigma-2 model: r²=0.83, q²=0.63) and sigma-1/sigma-2 selectivity (r²=0.72, q²=0.46) were derived using a series of α-tropanyl derivatives. The models provide pictures of the virtual receptor site (VRS) significant enough to attain a qualitative pharmacophoric representation of the sigma receptor. They give the internal geometrical relationships within two hydrophobic areas (hydrophobic-1 and -2) and a H-bond donor receptor region with which ligands establish non-covalent bonds.