title: 4-aroylpiperidines and 4-(α-hydroxyphenyl)piperidines as selective sigma-1 receptor ligands: synthesis, preliminary pharmacological evaluation and computational studies.
abstract: BACKGROUND
  Sigma (σ) receptors are membrane-bound proteins characterised by an unusual promiscuous ability to bind a wide variety of drugs and their high affinity for typical neuroleptic drugs, such as haloperidol, and their potential as alternative targets for antipsychotic agents. Sigma receptors display diverse biological activities and represent potential fruitful targets for therapeutic development in combating many human diseases. Therefore, they present an interesting avenue for further exploration. It was our goal to evaluate the potential of ring opened spipethiane (1) analogues as functional ligands (agonists) for σ receptors by chemical modification.
  
  
  RESULTS
  Chemical modification of the core structure of the lead compound, (1), by replacement of the sulphur atom with a carbonyl group, hydroxyl group and 3-bromobenzylamine with the simultaneous presence of 4-fluorobenzoyl replacing the spirofusion afforded novel potent sigma-1 receptor ligands 7a-f, 8a-f and 9d-e. The sigma-1 receptor affinities of 7e, 8a and 8f were slightly lower than that of 1 and their selectivities for this receptor two to threefold greater than that of 1.
  
  
  CONCLUSIONS
  It was found that these compounds have higher selectivities for sigma-1 receptors compared to 1. Quantitatitive structure-activity relationship studies revealed that sigma-1 binding is driven by hydrophobic interactions.Graphical abstractIdentified pharmacophore features for sigma binding.
authors.affiliation: Department of Chemistry, Faculty of Science, University of Buea, P.O. Box 63, Buea, South West Region Cameroon.
authors.forename: Hermia N
authors.initials: HN
authors.lastname: Ikome
authors.affiliation: Department of Chemistry, Faculty of Science, University of Buea, P.O. Box 63, Buea, South West Region Cameroon ; Department of Pharmaceutical Chemistry, Martin-Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany.
authors.forename: Fidele
authors.identifier: 0000-0003-0795-394X
authors.initials: F
authors.lastname: Ntie-Kang
authors.affiliation: Biotechnology Unit, Department of Biochemistry and Molecular Biology, Faculty of Science, University of Buea, P.O.Box 63, Buea, South West Region Cameroon.
authors.forename: Moses N
authors.initials: MN
authors.lastname: Ngemenya
authors.affiliation: Department of Radiology, University of Washington School of Medicine, Seattle, USA.
authors.forename: Zhude
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Department of Radiology, University of Washington School of Medicine, Seattle, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: Department of Chemistry, Faculty of Science, University of Buea, P.O. Box 63, Buea, South West Region Cameroon.
authors.forename: Simon M N
authors.initials: SM
authors.lastname: Efange
keywords: Pharmacophore; Piperidines; QSAR; Sigma-1 binding