Development of Tetrahydroindazole‐Based Potent and Selective Sigma‐2 Receptor Ligands

Iyamu, Iredia D.; Lv, Wei; Malik, Neha; Mishra, Rama K.; Schiltz, Gary E.

doi:10.1002/cmdc.201900203

Cited by 5 publications

(3 citation statements)

References 42 publications

(35 reference statements)

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“…Compounds NUCC-54129, NUCC-200823, NUCC-176289 and other NUCC analogs were synthesized according to methods described in US Patent 10,435,375 and in ( Iyamu et al, 2019a , 2019b ). NUCC analogs were dissolved in 20% DMSO and 80% water.…”

Section: Methodsmentioning

confidence: 99%

Effects of Small Molecule Ligands on ACKR3 Receptors

et al. 2022

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Chemokines such as Stromal Derived Factor 1 (SDF-1 or CXCL12) and their G protein coupled receptors (GPCRs) are well known regulators of the development and functions of numerous tissues. CXCL12 has two receptors: CXCR4 and ACKR3 or CXCR7. ACKR3 has been described as an atypical "biased" receptor because it does not appear to signal through G proteins and instead, signals solely through the β-arrestin pathway. In support of this conclusion, we have shown that ACKR3 is unable to signal through any of the known mammalian G α isoforms and have generated a comprehensive map of the G α activation by CXCL12/CXCR4.We also synthesized a series of small molecule ligands which acted as selective agonists for ACKR3 as assessed by their ability to recruit β-arrestin to the receptor. Using select point mutations, we studied the molecular characteristics that determine the ability of small molecules to activate ACKR3 receptors, revealing a key role for the deeper binding pocket composed of residues in the transmembrane domains of ACKR3. The development of more selective ACKR3 ligands should allow us to better appreciate the unique roles of ACKR3 in the CXCL12/CXCR4/ACKR3 signaling axis and better understand the structural determinants for ACKR3 activation.

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Section: Methodsmentioning

confidence: 99%

Effects of Small Molecule Ligands on ACKR3 Receptors

et al. 2022

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“…On the other hand, the most recent σ 2 R ligands pharmacophore was published in 2019 by scientists from Northwestern University. 86 They developed a series of tetrahydroindazoles and used the obtained SAR data to build the model using the PHASE module as implemented in the Schrödinger software suite. This pharmacophore model consists of one PI group, one HYAr ring, and three HY moieties ( Figure 6 B).…”

Section: Pharmacophore Models For σR Ligandsmentioning

confidence: 99%

“…This ESTEVE pharmacophore outperformed previously published models and, according to the authors, showed better results than molecular docking. On the other hand, the most recent σ 2 R ligands pharmacophore was published in 2019 by scientists from Northwestern University . They developed a series of tetrahydroindazoles and used the obtained SAR data to build the model using the PHASE module as implemented in the Schrödinger software suite.…”

Section: Pharmacophore Models For σR Ligandsmentioning

confidence: 99%

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

et al. 2021

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Since their discovery as distinct receptor proteins, the specific physiopathological role of sigma receptors (σRs) has been deeply investigated. It has been reported that these proteins, classified into two subtypes indicated as σ 1 and σ 2 , might play a pivotal role in cancer growth, cell proliferation, and tumor aggressiveness. As a result, the development of selective σR ligands with potential antitumor properties attracted significant attention as an emerging theme in cancer research. This perspective deals with the recent advances of σR ligands as novel cytotoxic agents, covering articles published between 2010 and 2020. An up-to-date description of the medicinal chemistry of selective σ 1 R and σ 2 R ligands with antiproliferative and cytotoxic activities has been provided, including major pharmacophore models and comprehensive structure–activity relationships for each main class of σR ligands.

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Discovery of oxazolidinone-based heterocycles as subtype selective sigma-2 ligands

2022

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Alzheimer's disease is a major, unmet medical need that impacts 6 million people in the US alone. Therapeutic options are limited, and the root cause of this condition remains unclear. The Amyloid Hypothesis has been proposed as a means of explaining the formation of amyloid plaques in the brain of patient. The sigma-2 receptor was recently identified as a potential therapeutic target capable of arresting the formation of amyloid plaques. Herein, we report the identification of a series of novel, functionalized oxazolidin-2-ones sigma-2 ligands.

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Development of Tetrahydroindazole‐Based Potent and Selective Sigma‐2 Receptor Ligands

Cited by 5 publications

References 42 publications

Effects of Small Molecule Ligands on ACKR3 Receptors

Effects of Small Molecule Ligands on ACKR3 Receptors

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

Discovery of oxazolidinone-based heterocycles as subtype selective sigma-2 ligands

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