Abstract
BackgroundSigma (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.ResultsChemical 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.ConclusionsIt 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-016-0200-1) contains supplementary material, which is available to authorized users.
Highlights
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 poten‐ tial as alternative targets for antipsychotic agents
Compounds 7a–f, 8a–f and 9d–e were synthesized according to methods A–C reported in Scheme 1
Reaction of 4-(4-fluorobenzoyl)piperidine with various substituted benzyl halides in the presence of sodium acetate, in aqueous ethanol afforded the methanone analogues 7a–f
Summary
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 poten‐ tial 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. They present an interesting avenue for further exploration. Sigma (σ) receptors are membrane-bound proteins that bind several psychotropic drugs with high affinity [1]. They were initially proposed to be related to opioid receptors [2] but were later found to be a distinct. Σ1 receptor is believed to have a ligand binding profile such that (+)-benzomorphans are at least fivefold to tenfold more potent than their corresponding (−)-isomers [7]. The presence of a σ3 subtype has not been confirmed yet, even though its existence was proposed in a few papers [13,14,15]
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