Bridging Known and Unknown Unknowns: From Natural Products and Their Mimics to Unmet Needs in Neuroscience

Martin, Stephen F.

doi:10.1021/acs.accounts.1c00773

Cited by 8 publications

(11 citation statements)

References 72 publications

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“…Methanobenzazocines and norbenzomorphans represent two distinct chemotypes of biologically active ligands that bind selectively to σ 2 R/TMEM97 ( Supp Fig 2 ) (39, 40). The first group comprises UKH-1114, which alleviates mechanical hypersensitivity in a mouse model of neuropathic pain (3) and reduces neuronal toxicity in a model of Huntington’s disease (20).…”

Section: Resultsmentioning

confidence: 99%

“…We then assessed whether other compounds that bind to σ 2 R/TMEM97 inhibit the ISR and whether ISR inhibition is specific to σ 2 R/TMEM97 modulators that promote analgesia. The norbenzomorphans FEM-1689, SAS-0132 and DKR-1677 and methanobenzacocines UKH-1114 represent two structurally distinct chemotypes that interact with the binding site of σ 2 R/TMEM97 in different orientations (39). SAS-0132 was previously shown to inhibit the analgesic effects of UKH-1114, which is a homolog of FEM-1689, suggesting that these two classes of molecules may exert opposing effects on σ 2 R/TMEM97 biology.…”

Section: Norbenzomorphan σ 2 R/tmem97 Ligands Sas-0132 and Dkr-1677 E...mentioning

confidence: 99%

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Highly specific σ₂R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response

Yousuf

Sahn

David

et al. 2023

Preprint

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The Sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands produce analgesia in mouse neuropathic pain models with a time course wherein analgesic onset is 24 hours following dosing. We sought to understand this unique anti-neuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons. Using male and female conventional knockout (KO) mice for Tmem97, we find that a novel σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce analgesia in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion (DRG) neurons, we demonstrate that FEM-1689 inhibits the integrated stress response and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

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Section: Resultsmentioning

confidence: 99%

Section: Norbenzomorphan σ 2 R/tmem97 Ligands Sas-0132 and Dkr-1677 E...mentioning

confidence: 99%

Highly specific σ₂R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response

Yousuf

Sahn

David

et al. 2023

Preprint

Self Cite

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“…Finding the vocabulary of so theories useful to explain the results of hard theory is related to one of the forms of knowledge, sometimes called "unknown unknowns." 216 According to Drew, "Unknown unknowns are pieces of knowledge that we do not have and equally are unaware that we don't have it. This is information that may be beyond our comprehension and indeed beyond our wildest dreams.…”

Section: Steric Effects Electronic Effectsmentioning

confidence: 99%

“…Finding the vocabulary of soft theories useful to explain the results of hard theory is related to one of the forms of knowledge, sometimes called “unknown unknowns.” 216 According to Drew,…”

Section: When the Language Of Soft Theory Is Called Upon To Explain H...mentioning

confidence: 99%

Understanding chemistry: from “heuristic (soft) explanations and reasoning by analogy” to “quantum chemistry”

Seeman

Tantillo

2022

Chem. Sci.

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“…However, the specific biological and molecular functions of S2R are still poorly understood, likely because it was only recently found to be coded by the TMEM97 gene [ 5 ]. Although the role of S2R/TMEM97 in the retina has been underexplored [ 17 ], there is evidence that S2R modulators could be neuroprotective for the brain [ 11 , 18 ] and/or retinal ganglion cells [ 19 ]. In an oxidant-induced retinal degeneration model, we observed that photoreceptor loss was exacerbated in Tmem97 −/− mice compared to Tmem97 +/+ mice [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Retinal Photoreceptor Protection in an AMD-Related Mouse Model by Selective Sigma-1 or Sigma-2 Receptor Modulation

Mavlyutov

Liu

et al. 2022

Genes

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The structurally and genetically distinct sigma-1 receptor (S1R) and sigma-2 receptor (S2R) comprise a unique class of drug binding sites. Their alleles are associated with human diseases involving neuronal systems, such as age-related macular degeneration (AMD) characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. Previous studies have suggested neuroprotective benefits for the brain and retina from pharmacological modulation of S1R and/or S2R. However, the effect of such modulation on AMD pathology remains underexplored. Here, we evaluated S1R- or S2R-selective modulation in an AMD-related model of Abca4−/−Rdh8−/− mice with a disrupted visual cycle that predisposes RPE and photoreceptors to illumination-induced damage. For S1R modulation, we used (+)-pentazocine, which is a high-affinity S1R-selective drug. For S2R modulation, we chose CM398, a high-affinity and highly S2R-selective ligand with drug-like properties. Abca4−/−Rdh8−/− mice received a single i.p. injection of (+)-pentazocine or CM398 or vehicle 30 min before illumination. Pretreatment with (+)-pentazocine improved electroretinogram a- and b-waves compared to that with vehicle. Consistently, in another AMD-related mouse model induced by tail-vein injected NaIO3, S1R genetic ablation aggravated photoreceptor loss. In Abca4−/−Rdh8−/− mice, pretreatment with CM398 appeared to partially avert illumination-induced photoreceptor loss and autofluorescent granule formation that signals RPE damage, as revealed by optical coherence tomography. Thus, this study using AMD-related models provides evidence of photoreceptor protection afforded by selective modulation of S1R or S2R.

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Bridging Known and Unknown Unknowns: From Natural Products and Their Mimics to Unmet Needs in Neuroscience

Abstract: This study showed for the f irst time that small molecules that bind selectively to σ 2 R/ TMEM97 have potent antinociceptive ef fects, thus demonstrating the potential of targeting σ 2 R/TMEM97 as a new non-opioid approach to treat neuropathic pain.

Cited by 8 publications

References 72 publications

Highly specific σ₂R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response

Highly specific σ₂R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response

Understanding chemistry: from “heuristic (soft) explanations and reasoning by analogy” to “quantum chemistry”

Retinal Photoreceptor Protection in an AMD-Related Mouse Model by Selective Sigma-1 or Sigma-2 Receptor Modulation

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Bridging Known and Unknown Unknowns: From Natural Products and Their Mimics to Unmet Needs in Neuroscience

Abstract: This study showed for the f irst time that small molecules that bind selectively to σ 2 R/ TMEM97 have potent antinociceptive ef fects, thus demonstrating the potential of targeting σ 2 R/TMEM97 as a new non-opioid approach to treat neuropathic pain.

Cited by 8 publications

References 72 publications

Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response

Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response

Understanding chemistry: from “heuristic (soft) explanations and reasoning by analogy” to “quantum chemistry”

Retinal Photoreceptor Protection in an AMD-Related Mouse Model by Selective Sigma-1 or Sigma-2 Receptor Modulation

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Highly specific σ₂R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response

Highly specific σ₂R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response