Identification, pharmacological evaluation and binding mode analysis of novel chromene and chromane based σ1 receptor ligands

Abstract

A set of aminoethyl substituted chromenes 3 and chromanes 4, originally developed as antiprotozoal drugs was evaluated as novel types of σ1 receptor ligands. Analysis of SAR showed that chromenes 3 have a higher σ1 affinity than chromanes 4. A distance of four bond lengths between the basic amino moiety and the phenyl ring (3c), an alicyclic N-substituent such as the cyclohexylmethyl moiety (3l), and methylation of the secondary amine to afford a tertiary amine (3n) result in very high σ1 affinity and selectivity over the σ2 subtype. Compounds 3a–n and 4a–e were docked into the putative binding site of the σ1 receptor model and the relevant binding mode was analyzed and scored. Specifically, for the best σ1 ligand 3n, a salt bridge between Asp126 and the protonated amino group, an H-bond between the receptor backbone NH group (Ala122–Glu123) and the methoxy moiety of 3n, a lipophilic protein cavity encasing the chromene ring, and a T-shaped π–π stacking between the indole ring of Trp121 and the phenyl ring of 3n represent the most important ligand/protein stabilizing interactions. The binding pose of 3n was compared with the binding poses of the non-methylated chromene 3c, the saturated chromane 4c, and the N-cyclohexylmethyl derivative 3l. The contribution of the single amino acids to the overall free binding enthalpy was analyzed.