Investigation of σ receptors agonist/antagonist activity through N-(6-methoxytetralin-1-yl)- and N-(6-methoxynaphthalen-1-yl)alkyl derivatives of polymethylpiperidines

doi:10.1016/j.bmc.2013.01.034

Bioorganic & Medicinal Chemistry

Volume 21, Issue 7, 1 April 2013, Pages 1865-1869

https://doi.org/10.1016/j.bmc.2013.01.034 Get rights and content

Abstract

A series of polymethyl-substituted piperidines linked to either a 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl or a 6-methoxynaphthalen-1-yl moiety was generated with the aim of verifying a previously generated hypothesis: tetralin and naphthalene nuclei confer opposite activity at the σ₁ receptor. Compounds 6, 9 and 10 displayed appreciable affinity at both σ subtypes, but none of the novel compounds displayed significant antiproliferative activity in MCF7wt and MCF7σ1 cell lines. The effect on bradikynin-triggered Ca²⁺ mobilization was studied as a methodology to suggest σ receptors mediated activity.

Graphical abstract

Introduction

Sigma receptor subtypes (σ₁ and σ₂) are potential targets for the diagnosis and therapy of several diseases.1, 2 In particular, the σ₁ subtype is involved in CNS pathologies such as schizophrenia, depression, Alzheimer’s and Parkinson’s diseases and it is endowed with neuroprotective and neuroregulative functions.3, 4, 5 Therefore, the diagnostic and therapeutic potentials that σ₁ ligands possess keep interest in σ₁ receptor research high, although the precise mechanism of action by which σ₁ protein exerts its effects needs thorough elucidation. On the basis of previous Structure–Affinity Relationship (SAfiR) studies, we developed a series of high affinity and highly selective σ₁ ligands in which a basic piperidine moiety was connected through a propyl or butyl linker to either a 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl or a 6-methoxynaphthalen-1-yl hydrophobic core (general structure in Fig. 1).⁶

Interestingly, the former hydrophobic moiety (tetralin nucleus) conferred agonist activity measured as lack of antiproliferative activity in σ₁ receptor overexpressing cancer cells), whereas the latter (naphthalene nucleus) conferred antagonist action (antiproliferative activity in the same cells). With the aim of confirming this trend, we developed a small series of polymethyl-substituted piperidines linked to both moieties mentioned above. If this trend was confirmed, useful tools to address the development of σ₁ agonists or antagonists could be provided. These novel compounds may also help to explore how much steric hindrance around the piperidine N-atom is tolerated without losing σ receptor binding, potentially leading to σ₁ antagonist activity.

Section snippets

Chemistry

The synthesis of the final compounds 5–12 was achieved as depicted in Scheme 1 using a slight modification of the conventional method already described.⁶ Alkylation of commercially available cis-2,6-dimethylpiperidine or 2,2,6,6-tetramethylpiperidine with the previously reported haloalkyl derivatives 1–4⁶ afforded the final amine compounds which were converted to the corresponding hydrochloride salts (unless otherwise stated) and recrystallized from MeOH/Et₂O.

Radioligand binding

All newly synthesized compounds

Conclusions

In conclusion, in the polymethylpiperidine series, compounds with higher conformational freedom (butyl-chain derivatives) or with less steric hindrance around the piperidine N-atom (2,6-dimethylpiperidines) showed appreciable affinity for both σ receptors (6, 9 and 10). However, none of the novel compounds displayed significant antiproliferative effect in MCF7wt and MCF7σ1 cells, with only piperidine 6 and 10 showing a modest antiproliferative response in MCF7 cells. Therefore, no difference in

Chemistry

Column chromatography was performed with 1:30 ICN silica gel 60 Å (63–200 or 15–40 μm, respectively) as the stationary phase. Melting points were determined in open capillaries on a Gallenkamp electrothermal apparatus. Elemental analyses (C, H, N) were performed on a Eurovector Euro EA 3000 analyzer; the analytical results were within ±0.4% of the theoretical values. High performance liquid chromatography (HPLC) was performed on a Perkin–Elmer series 200 LC instrument using a Phenomenex Gemini

Acknowledgement

This work was supported by MIUR with Grant 2008LTY389_003.

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Development of novel phenoxyalkylpiperidines as high-affinity Sigma-1 (σ<inf>1</inf>) receptor ligands with potent anti-amnesic effect
2022, European Journal of Medicinal Chemistry
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In our search for high-affinity σ1 receptor ligands, we have identified 4-methylpiperidine as a chemotype that confers a potent binding to the receptor when linked through a 3- to 4-methylene chain to a hydrophobic portion such as tetralin/naphthalene nuclei or phenoxy rings [37,38]. While initial studies led us to hypothesize opposing functional behaviors for the tetralin-bearing compounds such as PB190 (σ1 receptor agonists) and the naphthalene-bearing compounds such as PB212 (σ1 receptor antagonists) [37], later studies contradicted this hypothesis (Fig. 1) [39]. It is worth noting that the concept of “agonist” versus “antagonist” for σ1 receptor ligands is quite elusive, as agonism involves ligand-induced allosteric modulation of protein–protein interactions between the σ1 receptor and its client proteins, and assays that can predict such interactions are under development [40].
The sigma-1 (σ₁) receptor plays a significant role in many normal physiological functions and pathological disease states, and as such represents an attractive therapeutic target for both agonists and antagonists. Here, we describe a novel series of phenoxyalkylpiperidines based on the lead compound 1-[ω-(4-chlorophenoxy)ethyl]-4-methylpiperidine (1a) in which the degree of methylation at the carbon atoms alpha to the piperidine nitrogen was systematically varied. The affinity at σ₁ and σ₂ receptors and at Δ⁸-Δ⁷ sterol isomerase (SI) ranged from subnanomolar to micromolar K_i values. While the highest-affinity was displayed at the σ₁, the increase of the degree of methylation in the piperidine ring progressively decreased the affinity. The subnanomolar affinity 1a and 1-[ω-(4-methoxyphenoxy)ethyl]-4-methylpiperidine (1b) displayed potent anti-amnesic effects associated with σ₁ receptor agonism, in two memory tests. Automated receptor–small-molecule ligand docking provided a molecular structure-based rationale for the agonistic effects of 1a and 1b. Overall, the class of the phenoxyalkylpiperidines holds potential for the development of high affinity σ₁ receptor agonists, and compound 1a, that appears as the best in class (exceeding by far the activity of the reference compound PRE-084) deserves further investigation.
The σ<inf>1</inf> receptor agonist (+)-pentazocine increases store-operated Ca<sup>2+</sup> entry in MCF7σ<inf>1</inf> and SK-N-SH cell lines
2017, Pharmacological Reports
Citation Excerpt :
The endoplasmic reticulum (ER) releases Ca2+ in the presence of specific extracellular ligands which engage the phospholipase C/inositol triphosphate pathway. Such ER-Ca2+ release: (a) is increased by the σ1 receptor agonist (+)-pentazocine in NG108 [3], SK-N-SH [4], and MCF7σ1 cells [5]; (b) is decreased by the σ1 receptor antagonists PB212 and BD1063 in SK-N-SH [4] and MCF7σ1 cells [6], respectively; (c) is decreased by the σ2 receptor agonist PB28 in MCF7 cells [6]. On the plasma membrane, the σ1 receptor agonists potentiated the intracellular Ca2+ influx induced by stimulation of NMDA receptor, in rat hippocampal neurons [7], but inhibited the Ca2+ influx through L-type Ca2+-channels in retinal ganglion cells [8].
The intracellular [Ca²⁺] is modulated by σ receptors. An important component of the cellular machinery governing the intracellular [Ca²⁺] is Store-Operated Calcium Entry (SOCE). Here we want to investigate whether ligands of σ receptors affect SOCE.
The intracellular [Ca²⁺] was monitored, with the fluorescent Ca²⁺-sensitive probe Fura-2, in four cell lines with a different expression of σ receptors, namely MCF7 (expressing σ₁ receptors with a low density and overexpressing σ₂ receptors), MCF7σ₁ (overexpressing σ₁ receptors), SK-N-SH, and HT-29.
When thapsigargin was used to deplete intracellular Ca²⁺ stores, in a Ca²⁺-free incubation medium, the Ca²⁺ influx (following Ca²⁺ re-addition) was significantly increased by 1 μM (+)-pentazocine (σ₁ receptor agonist) in MCF7σ₁ (by 22.5%) and SK-N-SH (by 45.6%), but not in HT-29 and MCF7 cells. We have used, as a second approach, the “Mn²⁺ quenching” protocol. In MCF7σ₁ cells, after thapsigargin treatment, the fluorescence quenching induced by Mn²⁺ influx (evidence of Ca²⁺ influx) was significantly increased (by 25.8%) by 1 μM (+)-pentazocine, significantly decreased (by 18.0%) by BD1063 (σ₁ receptor antagonist), and not affected by the presence of both ligands. These effects were not observed in MCF7 cells. Finally, in MCF7 cells, 1 μM PB28 (σ₂ receptor agonist), did not affect both the Ca²⁺ response after Ca²⁺ re-addition and the fluorescence quenching induced by Mn²⁺ influx.
We propose that the σ₁ receptor agonist (+)-pentazocine increases SOCE in MCF7σ₁ and SK-N-SH cell lines. The σ₂ receptor agonist PB28 does not affect SOCE in MCF7 cells.
The effects of new sigma (σ) receptor ligands, PB190 and PB212, in the models predictive of antidepressant activity
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However, this mechanism of action of σ receptor ligands is not clear in detail. Among all the piperidines synthesized by Berardi and coworkers [5,6,10,21], PB212 and PB190 (a naphthalene derivative and its tetralin counterpart, respectively) were selected as the compounds with an optimal binding profile, displaying a good affinity and selectivity for σ1 receptors. In addition naphthalene derivative PB212 was demonstrated to be a σ1 receptor antagonist through the bradykinin induced Ca2+-release assay [12], whereas PB190 was claimed to be a σ1 receptor agonist [6].
A number of σ receptor ligands have been demonstrated to possess antidepressant-like effect in some experimental paradigms (e.g. forced swim test, tail suspension test, olfactory bulbectomy model, conditioned fear stress). The objective of the present study was to find out whether PB190 and PB212, new σ₁ receptor ligands, show the effects in some models predictive of antidepressant activity.
The impact of PB190 and PB212 on the immobility time in the forced swim test (FST) and tail suspension test (TST) was assessed in C57BL/6J male mice. Extracellular bradykinin triggers a transient increase in intracellular calcium concentration by activating the phospholipase C/IP₃ pathway. The intracellular calcium concentration was estimated with the dual wavelength ratiometric probe Fura-2.
In the FST model, PB190 showed a moderate antidepressant-like effect (only in the dose of 3 mg/kg) which was enhanced by joint treatment with amantadine (AMA), 10 mg/kg (inactive per se). The decrease in the immobility time induced by the combined treatment with PB190 and AMA was counteracted by PB212 and by BD1047, a σ₁-receptor antagonist. The in vitro studies indicated that Ca²⁺-response was increased by 1 μM PB190, like by the σ₁-agonist (+)-pentazocine, while 1 μM PB212 behaved line σ₁-antagonist, BD1063. On the other hand, 100 μM PB190 negatively affected the Ca²⁺-response after bradykinin.
The obtained results: 1/indicated that in the in vivo conditions PB190 behaved as a σ₁-receptor agonist while PB212 counteracted its effect, confirming the in vitro data; 2/gave support to the hypothesis that σ₁-receptors might be one of possible mechanisms by which drugs induce antidepressant-like activity; 3/revealed that this effect may be potentiated by NMDA receptor antagonists, e.g. AMA.
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Investigation of σ receptors agonist/antagonist activity through N-(6-methoxytetralin-1-yl)- and N-(6-methoxynaphthalen-1-yl)alkyl derivatives of polymethylpiperidines

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Radioligand binding

Conclusions

Chemistry

Acknowledgement

J. Biol. Chem.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Rep.

Eur. J. Pharmacol.

Cell Calcium

Curr. Pharm. Des.

Curr. Neuropharmacol.