Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands

Wu, Zhiping; Song, Shu-Yong; Li, Li; Lu, He‐Lin; Lieberman, Brian P.; Huang, Yanqi; Mach, Robert H.

doi:10.1016/j.bmc.2015.02.012

Cited by 15 publications

(8 citation statements)

References 47 publications

(66 reference statements)

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“…The σ 2 receptor is known to be an 18-to 21-kDa membrane protein (3), and ligand-binding studies have shown that it is highly expressed in the liver and kidney (11,12) and in the CNS (13) as well as in several cancer cell lines (14) and proliferating tumors (15). These intriguing features and the potential medical applications of compounds that modulate σ 2 have stimulated a number of investigations directed toward the development of σ 2 receptor ligands, and numerous high-affinity and subtypeselective compounds have been developed as a result (12,(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Identification of the gene that codes for the σ ₂ receptor

Alon

Schmidt

Wood

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

239

280

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The σ receptor is an enigmatic protein that has attracted significant attention because of its involvement in diseases as diverse as cancer and neurological disorders. Unlike virtually all other receptors of medical interest, it has eluded molecular cloning since its discovery, and the gene that codes for the receptor remains unknown, precluding the use of modern biological methods to study its function. Using a chemical biology approach, we purified the σ receptor from tissue, revealing its identity as TMEM97, an endoplasmic reticulum-resident transmembrane protein that regulates the sterol transporter NPC1. We show that TMEM97 possesses the full suite of molecular properties that define the σ receptor, and we identify Asp29 and Asp56 as essential for ligand recognition. Cloning the σ receptor resolves a longstanding mystery and will enable therapeutic targeting of this potential drug target.

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mentioning

confidence: 99%

Identification of the gene that codes for the σ ₂ receptor

Alon

Schmidt

Wood

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

239

280

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“…To assess the quality of the pharmacophore models, 191 active S2R ligands were pooled from the literature with pKi cutoff of 6.0 (dataset P2). These compounds belong to three major scaffolds of S2R ligands, including siramesine analogs [ 43 ], piperazine [ 31 , 39 , 44 , 45 , 46 , 47 ], and tetrahydroisoquinolinyl [ 31 , 35 , 48 , 49 , 50 , 51 , 52 , 53 ]. Another core scaffold of S2R analogs, a conformationally restricted amine, was excluded from this study due to its high molecular weight and highly complex structure [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

QSAR-Based Computational Approaches to Accelerate the Discovery of Sigma-2 Receptor (S2R) Ligands as Therapeutic Drugs

Dong

Peng

et al. 2021

Molecules

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S2R overexpression is associated with various forms of cancer as well as both neuropsychiatric disorders (e.g., schizophrenia) and neurodegenerative diseases (Alzheimer’s disease: AD). In the present study, three ligand-based methods (QSAR modeling, pharmacophore mapping, and shape-based screening) were implemented to select putative S2R ligands from the DrugBank library comprising 2000+ entries. Four separate optimization algorithms (i.e., stepwise regression, Lasso, genetic algorithm (GA), and a customized extension of GA called GreedGene) were adapted to select descriptors for the QSAR models. The subsequent biological evaluation of selected compounds revealed that three FDA-approved drugs for unrelated therapeutic indications exhibited sub-1 uM binding affinity for S2R. In particular, the antidepressant drug nefazodone elicited a S2R binding affinity Ki = 140 nM. A total of 159 unique S2R ligands were retrieved from 16 publications for model building, validation, and testing. To our best knowledge, the present report represents the first case to develop comprehensive QSAR models sourced by pooling and curating a large assemblage of structurally diverse S2R ligands, which should prove useful for identifying new drug leads and predicting their S2R binding affinity prior to the resource-demanding tasks of chemical synthesis and biological evaluation.

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“…3-Azabicylo[3.3.1]nonane is the core substructure of the marine natural product; Haliclonin A (Figure 1) [8,9]. 9-Azabicyclo[3.3.1]nonane derivatives possess cytotoxic [10], dopamine D3 receptor ligands [11], high sigma-2 receptor affinities [12], and are used for the treatment of diabetes mellitus [13]. Furthermore, 1,4-diazabicyclo[3.3.1]nonane derivatives are reported to exhibit high in vivo affinity and selectivity for the dopamine transporter (DAT) blockers [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…Some 1,3,5,7-tetraazabicyclo[3.3.1]nonane derivatives have antithrombotic activities [29]. Although tremendous progress has been achieved in the synthesis of mono-, di-, and tri-azabicyclo[3.3.1]nonanes [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27], the synthesis of tetra- and penta-azabicyclo[3.3.1]nonane frameworks has rarely been disclosed in the literature [30,31,32,33].…”

Section: Introductionmentioning

confidence: 99%

Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms

et al. 2019

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Reactions of a series of 3-oxo-2-arylhydrazonopropanal derivatives with two molar ratio of ammonium acetate afforded a library of tetrasubstituted 2,3,6,7,9-pentaazabicyclo[3.3.1]nona- 3,7-diene derivatives in good to excellent isolated yields. The reaction was activated with triethylamine catalyst under three different heating modes: thermal, ultrasonic and microwave irradiating conditions in ethanol solvent. The structures of the isolated products were fully characterized by spectral and analytical data as well as X-ray single crystal of selected examples.

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Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands

Cited by 15 publications

References 47 publications

Identification of the gene that codes for the σ ₂ receptor

Identification of the gene that codes for the σ ₂ receptor

QSAR-Based Computational Approaches to Accelerate the Discovery of Sigma-2 Receptor (S2R) Ligands as Therapeutic Drugs

Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms

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Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands

Cited by 15 publications

References 47 publications

Identification of the gene that codes for the σ 2 receptor

Identification of the gene that codes for the σ 2 receptor

QSAR-Based Computational Approaches to Accelerate the Discovery of Sigma-2 Receptor (S2R) Ligands as Therapeutic Drugs

Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms

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Identification of the gene that codes for the σ ₂ receptor

Identification of the gene that codes for the σ ₂ receptor