scholarly journals Highly Specific Sigma Receptor Ligands Exhibit Anti-viral Properties in SARS-CoV-2 Infected Cells

Pathogens ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1514
Author(s):  
David A. Ostrov ◽  
Andrew P. Bluhm ◽  
Danmeng Li ◽  
Juveriya Qamar Khan ◽  
Megha Rohamare ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Sigma Receptor ◽  
Sigma Receptors ◽  
Genome Replication ◽  
Receptor Ligands ◽  
Sigma 1 Receptor ◽  
Binding Characteristics ◽  
Sigma Receptor Ligands ◽  
Prevention And Treatment ◽  
Sigma 1

(1) Background: There is a strong need for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. This study found antiviral activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66). (3) Results: Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling. (4) Conclusions: Sigma receptor ligands and drugs with off-target sigma receptor binding characteristics were effective at inhibiting SARS-CoV-2 infection in primate and human cells, representing a potential therapeutic avenue for COVID-19 prevention and treatment.

In Pursuit of Fluorinated Sigma Receptor Ligand Candidates Related to [18F]-FPS

2019 ◽  
Vol 72 (3) ◽  
pp. 213 ◽  
Author(s):  
Rasha S. Jwad ◽  
Alan H. C. Pang ◽  
Luke Hunter ◽  
Roger W. Read
Keyword(s):  
Functional Group ◽  
Ester Group ◽  
Sigma Receptor ◽  
Hydroxyl Group ◽  
Receptor Ligands ◽  
Literature Report ◽  
Sigma Receptor Ligands ◽  
Displacement Reactions ◽  
Sigma 1 ◽  
New Evidence

This paper describes the synthesis of N-arylmethyl(1-benzyl) and N-aroyl(1-benzoyl) 4-(4-fluoromethylphenoxymethyl)piperidines as potential sigma receptor ligands analogous to the potent and highly selective sigma-1 ligand [18F]-FPS, but with enhanced or alternative binding and transport profiles. The synthesis involves N-aroylation of 4-hydroxmethylpiperidine or ethyl nipecotate, functional group manipulation of the ester group or simple activation of the hydroxyl group to introduce the phenoxy component, and subsequent functional group manipulation to reduce the amide group and introduce the fluorine into the fluoromethyl substituent. In its development, the synthesis was found to require early N-aroylation of the piperidine precursor to avoid complications due to anchimeric assistance by its nitrogen in subsequent displacement reactions. New evidence is presented on the pathway followed in a literature report of direct displacement of a benzylic hydroxyl group by fluoride ion under Appel-like conditions. Relevant to the literature report, the halide ion in the fluoromethylphenoxy 1-benzylpiperidine derivatives was surprisingly labile to hydrolytic displacement on chromatography and this aspect is worthy of further study. Moreover, the NMR spectra of the amides were complicated by geometric isomerism about the amide C(O)–N bond, but detailed analysis of spectra from 2-anisoyl derivatives allowed the assignment of diastereomeric contributors to consistent, secondary atropisomerism about the aryl–C(O) bond.

scholarly journals Synthesis and evaluation of sigma receptor ligands

2010 ◽  
Author(s):  
◽  
Kuo-Hsien Fan
Keyword(s):  
Sigma Receptor ◽  
Imaging Agents ◽  
Receptor Ligands ◽  
Receptor Ligand ◽  
Sigma 1 Receptor ◽  
Lead Compounds ◽  
In Vivo Distribution ◽  
Sigma 1

Sigma receptors are unique binding sites located in the central nervous system (CNS) and peripheral organs. Two sigma receptor subtypes ([signma]1 and [sigma]2) have been described so far. It is known that the [sigma]1 receptor is involved in a number of CNS disorders and the [sigma]2 receptor is involved in tumor proliferation among others. Because of the important biological functions of the [sigma] receptor, development of structure activity relationships (SAR) can aid in the identification of potential medications and imaging agents. Three series of analogs based on three lead compounds have been synthesized and evaluated for their in vitro affinity and selectivity for the [sigma]1 and [sigma]2 subtypes. Lead I is a selective [sigma]1 receptor ligand with anti-cocaine activity, but its in vivo distribution is unknown. Our in vitro binding results showed that all the Lead I analogs are potent [sigma]1 receptor ligands. Furthermore, one of the Lead I analogs was radioiodinated and evaluated for its in vivo distribution. In vivo evaluation of the radioiodinated Lead I analog has shown high brain uptake and specific binding to [sigma]1 receptor of the radioligand. Lead II is also a selective [sigma]1 receptor ligand and radioiodinated Lead II has been shown to be a potential imaging agent for the [sigma]1 receptor. Two of the Lead II analogs were shown to be potent [sigma]1 receptor ligands. The radioiodinated Lead II analogs were demonstrated to be potential imaging agents for [sigma]1 receptor in vivo. Lead III is one of the most selective [sigma]2 receptor ligands known to date. Only one of the newly synthesized Lead III analogs was found to be a selective [sigma]2 receptor ligand. The SAR study of Lead III analogs successfully indentified the important structural features in Lead III for [sigma]2 receptor binding. To summarize, the SAR studies based on the lead compounds have generated useful information and three potential [sigma]1 imaging agents were prepared in the studies.

The Sigma-1 Receptor Ligands Chlorpromazine and Trifluoperazine Inhibit Na+ Transport in Frog Skin Epithelium

BIOPHYSICS ◽  
2020 ◽  
Vol 65 (5) ◽  
pp. 784-787
Author(s):  
A. V. Melnitskaya ◽  
Z. I. Krutetskaya ◽  
V. G. Antonov ◽  
N. I. Krutetskaya
Keyword(s):  
Frog Skin ◽  
Receptor Ligands ◽  
Na Transport ◽  
Sigma 1 Receptor ◽  
Skin Epithelium ◽  
Frog Skin Epithelium ◽  
Sigma 1

scholarly journals Recent Advances in the Development of Sigma Receptor Ligands as Cytotoxic Agents: A Medicinal Chemistry Perspective

2021 ◽  
Author(s):  
Antonino N. Fallica ◽  
Valeria Pittalà ◽  
Maria N. Modica ◽  
Loredana Salerno ◽  
Giuseppe Romeo ◽  
...  
Keyword(s):  
Medicinal Chemistry ◽  
Cytotoxic Agents ◽  
Sigma Receptor ◽  
Receptor Ligands ◽  
Sigma Receptor Ligands ◽  
Recent Advances
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