In This Issue Cite This: ACS Chem. Neurosci. 2019, 10, 5−5
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REPURPOSING SSRIs
tional” theory of olfaction. These results support the conclusion that if mammals can perceive deuterated odorants differently, the difference may arise from the receptorindependent steps of olfaction.
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■ Alzheimer’s disease (AD) is a major challenge to treat due to its complexity. In the past decade, several attempts on developing a potential cure or new strategies have failed. In addition, many elderly patients with AD also suffer from depression and are consequently on antidepressant medications, such as selective serotonin reuptake inhibitors (SSRIs). Now, Tin and co-workers (DOI: 10.1021/acschemneuro.8b00160) explore the possibility of “repurposing” FDAapproved drugs such as SSRIs for potential therapeutic applications in AD. The authors investigated the effects of SSRIs fluvoxamine (Luvox), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and escitalopram (Lexapro) on Aβ aggregation, using a combination of biochemical, biophysical, and computational methodology including aggregation kinetics, transmission electron microscopy, molecular docking, and pharmacophore modeling studies. They found that three SSRIs, fluoxetine, paroxetine, and sertraline, can prevent the aggregation of Aβ42 protein and its fibrillogenesis by direct interactions and binding
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EXPLORING THE LYSOLIPID−GPR55 INTERACTION
G protein-coupled receptor 55 (GPR55) is highly expressed throughout the body, including the central and peripheral nervous system. GPR55 is implicated in diseases such as neuropathic pain, obesity, and cancer, and thus represents an important target for drug discovery. It was recently demonstrated that GPR55 plays an essential role in embryonic development, through activation by lysophospholipids. Understanding the lysolipid-GPR55 interaction can lead to greater understanding of GPR55 pharmacology. In this issue, Guy and co-workers (DOI: 10.1021/ acschemneuro.8b00505) use primary sensory neurons that endogenously express GPR55 to screen lysolipid ligands. The results demonstrate that the most commonly reported ligand for GPR55, lysophosphatidylinositol, acts in a GPR55independent manner in this system. Instead, the CNS-specific lysolipid, lysophosphatidylglucoside, demonstrates agonist activity at GPR55, highlighting the preference for gluco- over inositol- and galacto-configured headgroups. The authors also report the first total chemical synthesis and complete spectroscopic characterization of lysophosphatidylglucoside, enabling the preparation of a set of lysophosphatidylglucoside analogues for biological testing. Molecular dynamics simulations provide insight into the structural basis of lysolipidGPR55 interaction.
SNIFFING OUT THE DETAILS OF OLFACTION
The olfactory receptors account for almost half of the Gprotein-coupled receptors in humans and other mammals. They are expressed in the olfactory epithelium and mediate the transduction of odorant chemical information into the neuronal signal that leads to the sensation of smell. No olfactory receptor structures have been solved, leaving uncertainty in the molecular recognition details of olfaction. In this issue, Na et al. (DOI: 10.1021/acschemneuro.8b00416) evaluate the ability of olfactory receptors expressed in mouse sensory neurons to distinguish odorants bearing hydrogen from their deuterated counterparts. Nearly all of the 1610 odorant-responding neurons tested failed to distinguish D- and H-isotopologues; however, 0.8% of responding neurons were able to discriminate H from D. The authors show that, in general, olfactory receptors do not discriminate H from D in live sensory neurons, disagreeing somewhat with the “vibra© 2019 American Chemical Society
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Published: January 16, 2019 5
DOI: 10.1021/acschemneuro.8b00731 ACS Chem. Neurosci. 2019, 10, 5−5
