title: 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.
authors.affiliation: MOSE-DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Dipak
authors.initials: D
authors.lastname: Harel
authors.affiliation: MOSE-DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Marson
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.affiliation: Institut für Pharmazeutische Biologie und Phytochemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Schmidt
authors.affiliation: MOSE-DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University Münster, Germany. Electronic address: wuensch@uni-muenster.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D002839:Chromans / Q000737:chemistry* / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017480:Receptors, sigma / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002839:Chromans; D008024:Ligands; D017480:Receptors, sigma
keywords: Binding pose; Docking studies; Molecular dynamics simulations; Molecular interactions; Structure affinity relationships; σ(1) receptor ligands