4-aroylpiperidines and 4-(α-hydroxyphenyl)piperidines as selective sigma-1 receptor ligands: synthesis, preliminary pharmacological evaluation and computational studies

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.

Structurally simple synthetic 1, 4-disubstituted piperidines with high selectivity for resistant Plasmodium falciparum

“…Also, the methanol analogues were the least cytotoxic as seen from their relatively higher SI values (Table 3 ). These compounds were designed as 1, 4-disubstituted piperidine analogues inspired by spipethiane, a molecule with a restricted conformation due to spirofusion in its structure and is selective for sigma-1 receptors which elicit diverse biological effects [ 12 ]. Given the presence of a piperidyl fragment in spipethiane, the latter may well turn out to be an antiplasmodial agent.…”

“…The synthesis of the 14 piperidines has been described in detail [ 12 ]. The compounds are based on a common parent skeleton shown in Fig.…”

“…When tested, these compounds displayed high affinity for sigma receptors. In a bid to further explore the pharmacological potential of these compounds and in view of the wide range of biological activities reported for substituted piperidines, these 1, 4-piperidines were also screened for antiplasmodial activity as part of our continuing search for efficacious antimalarials [ 12 ].…”

The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review

“…In addition, compound 76 displayed a very low affinity for D1, D2, and 5HT1A receptors, thus confirming its selectivity for the σ1 receptor and the possibility to label compound 76 with 11 C or 18 F without affecting the receptor binding process or the imaging signals for PET studies. In 2016, the research group of Professor Efange sought to elucidate the role of spirofusion of spipethiane (compound 77, Figure 18) in the biological activity of the σ1 receptor [19]. Spipethiane ( 77) is a very potent and selective ligand of the σ1 receptor, with Ki values of 0.50 and 416 nM for the σ1 and σ2 receptors, respectively [107].…”

Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases

“…The 5-pyridyl substituted thiazole derivatives 75 and 76 were the most promising candidates and exhibit low nanomolar affinity at the σ 1 receptor ( K i = 1.3–1.9 nM), high σ 1 /σ 2 selectivity (>1500-fold), and good ligand efficiency . Additionally, Efange and colleagues described a series of ring-opening spipethiane analogues by replacing the sulfur atom with a carbonyl ( 77 ), hydroxylmethenyl ( 78 – 79 ), or 3-bromobenzylamine ( 80 ) bridge (Figure ). Although the σ 1 receptor affinities of 77 – 80 were slightly lower than that of spipethiane, their good σ 1 receptor selectivity over σ 2 receptors was achieved.…”