Editorial pubs.acs.org/chemneuro
Editors’ Favorites of 2016
T
he year 2016 was a tremendous year for ACS Chemical Neuroscience, with a record breaking number of citations, submissions at an all-time high, and an abundance of high impact, important papers. This year, I asked all the Associate Editors to pick their favorite papers of 2016 to highlight here, and provide additional exposure for these exciting papers. Clearly, this was a challenging proposition, as there were so many amazing and impactful papers published in ACS Chemical Neuroscience in 2016. My first pick as a 2016 favorite comes from Dr. Travis Wager and co-workers at Pfizer, where they further expand on, and show applications in drug discovery for, their Central Nervous System Multiparameter Optimization (CNS MPO) Desirability tool (DOI: 10.1021/acschemneuro.6b00029). This was a follow-up to the two most cited papers in the history of ACS Chemical Neuroscience where CNS MPO was first introduced in 2010.1,2 Within Pfizer, the CNS MPO tool has helped to increase the percentage of clinical candidates that exhibit a preferred alignment of ADME attributes, afford CNS penetration, and reside in lower-risk safety space (low ClogP and high TPSA). They also found that the CNS MPO tool reduced the number of compounds submitted to exploratory toxicity studies and, importantly, increased the survival of our drug candidates through regulatory toxicology into First in Human studies. Overall, the CNS MPO algorithm has improved the prioritization of design ideas and the quality of the compounds nominated for clinical development. Here, Wager and co-workers really show the tool at work, with statistics for how candidates compare to CNS MPO candidates and commercial CNS drugs. I especially like this as it moves beyond “rules” to a flexible alignment that brings in multiple considerations in CNS drug/ligand design, and this tool has been well adopted by the medicinal chemistry community, as well as expanded.3 Craig W. Lindsley, Editor-in-Chief
electrophysiology experiments reveal the inner pore region of the channel as the ligand binding site of these minimum pharmacophores of BTX, analogous to BTX, alkaloid toxins, and local anesthetics. The fact that they share the same binding site as BTX but confer a switch in the mode of pharmacology is intriguing. This exceptional work highlights the transforming power of synthetic chemistry applied to CNS problems and the value of generating analogues of natural products. Craig W. Lindsley, Editor-in-Chief
In 2016, Prof. Dirk Trauner and his team reported a photochromic ligand for AMPA receptors and demonstrated that it could be used to control ATA activity in light-insensitive mouse retinae (DOI: 10.1021/acschemneuro.5b00234). The creativity of the Trauner lab for the use of photochromic ligands never ceases to amaze me, and in 2016 we gained a glimpse of one of the major application areas that the lab is pursuingin truly visionary fashion, pun intended. The publication follows other major contributions to the journal including recent photochromic ligands for nicotinic acetylcholine receptors4 and voltage gated ion channels.5 There is much work to be done to understand the retinal system and how to manipulate it to restore vision, but I must say that I have an affinity for novel chemistry done in the pursuit of addressing a truly unmet biomedical need and I am looking forward to what we might get to see in 2017. Jacob M. Hooker, Associate Editor
The Bonnin lab contributed a fascinating article on the fate of citalopram (and antidepressant SSRI) during mouse pregnancy (DOI: 10.1021/acschemneuro.5b00287). I am perhaps drawn to this article having realized (as a father) how few studies exist that explain the disposition of a psychoactive drug, or any drug for that matter, in a fetus during pregnancy. While extrapolation to humans may be difficult, studies like this one are critical so that we understand and appreciate that the modulation of neurochemistry with
My second pick as a 2016 favorite comes from Dr. Du Bois and co-workers from Stanford University, where an exceptional example of chemical neuroscience was showcased detailing inhibition of sodium ion channel function with truncated forms of Batrachotoxin (BTX), a natural product isolated from poison dart frogs (DOI: 10.1021/acschemneuro.6b00212). Here, they established that simplified analogues of BTX possessing the C/ D/E ring elements (e.g., the minimum pharmacophore) are low micromolar inhibitors of NaV subtypes (NaV1.2, NaV1.4, NaV1.5, and NaV1.7) as opposed to the NaV agonist activity displayed by BTX. Moreover, protein mutagenesis and © 2017 American Chemical Society
Published: January 18, 2017 1
DOI: 10.1021/acschemneuro.6b00461 ACS Chem. Neurosci. 2017, 8, 1−3
ACS Chemical Neuroscience
Editorial
reserve. By contrast, environmental influences including a healthy lower calorie diet, abundant exercise, and reduced stress have positive effects on adult neurogenesis and memory function. The authors review research that points to microglia as a key link between environmental factors and hippocampal function via microglial surveillance of the neurogenic niche, and release of soluble and extracellular vesicle signaling molecules. Maybe the next time you remember where you parked your car after you exit the gym, you have your microglia to thank. Anne M. Andrews, Associate Editor
drugs may have unintended consequences if we do not consider issues of sex differences6,7 and brain developmentI hope we see more contributions along these lines in 2017. Jacob M. Hooker, Associate Editor
My pick for Editors’ Favorites of 2016 is based upon work from Dr. Jennifer Whistler at the University of California at San Francisco (DOI: 10.1021/acschemneuro.6b00167). The treatment of acute and chronic pain is reliant at present upon opioid analgesics; however, the efficacy of these medications is compromised by the development of tolerance to their painkilling properties, as well as the epidemic of opioid use disorder, one of the top public health problems in the United States.8,9 Dr. Whistler and her team recognized that the prominent opioid therapeutics (e.g., morphine) are “biased” μ-opioid receptor agonists which preferentially stimulate G proteincoupled downstream signaling, but only weakly activate βarrestin signaling. Their goal is to pursue novel chemical entities which mimic the endogenous endorphins with “balanced” agonist actins at both G protein-coupled and βarrestin signaling, a profile which may reduce liability for analgesic tolerance and dependence. Turning to the sea for inspiration, alkaloids of marine sponges were screened for agonist actions at the μ-opioid receptor and the fascaplysins exhibited “balanced” activation of G protein-coupled and βarrestin signaling, a profile distinct from currently marked opioid analgesics. I am intrigued by the prospects of this new chemotype to result in novel approaches to pain management with reduced abuse liability. Kathryn A. Cunningham, Associate Editor
Controlling the activity of genetically defined and, thus, highly specific populations of neurons via light-mediated (optogenetic) or pharmacologic (chemogenetic) control is revolutionizing our ability to interrogate and to understand neural circuits in vivo. In this paper by Islam et al. (DOI: 10.1021/acschemneuro.6b00168), the authors report on the engineering and characterization of a number of human α1 glycine receptor Cl− channels. Two optimal mutants were identified. One was selectively permeable to Na+, while the other was highly Ca2+ permeant. Both engineered channels were activated by the drug ivermectin at low nanomolar concentrations. These mutants enabled neurons to be either depolarized at normal levels by Na+ influx or strongly depolarized via influx of Ca2+. Activation by Ca2+ caused neuronal death, analogous to apoptotic cell death hypothesized to be associated with various neurodegenerative disorders. The use of these receptor mutants in vivo is presaged by the authors’ report earlier this year of another glycine receptor mutant for in vivo neuronal silencing.11 Anne M. Andrews, Associate Editor
As 2016 comes to a close and many of us contemplate making (or renewing) New Year’s resolutions, there may be another reason to improve our diets, exercise routines, and stress coping skills. As described by Sierra and co-authors (DOI: 10.1021/acschemneuro.6b00009), these lifestyle factors affect more than our waistlines. Their paper focuses on reviewing the evidence for relationships between lifestyle, adult hippocampal neurogenesis, and a key intermediarymicroglia. The latter are brain immune cells that may regulate the birth, differentiation, and maturation of new neurons in the hippocampus. The hippocampus mediates the acquisition of spatial10 and emotional memory and adult neurogenesis is believed to contribute to hippocampal neuronal plasticity needed to generate and to store memories. Normal aging and, to a greater extent, neurodegenerative disorders reduce hippocampal function. However, individuals respond differently to these challenges, possibly due to variations in cognitive
Craig W. Lindsley, Editor-in-Chief Jacob M. Hooker, Associate Editor Kathryn A. Cunningham, Associate Editor Anne M. Andrews, Associate Editor
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AUTHOR INFORMATION
ORCID
Craig W. Lindsley: 0000-0003-0168-1445 Kathryn A. Cunningham: 0000-0002-4257-1739 2
DOI: 10.1021/acschemneuro.6b00461 ACS Chem. Neurosci. 2017, 8, 1−3
ACS Chemical Neuroscience
Editorial
Anne M. Andrews: 0000-0002-1961-4833 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) Wager, T. T., Chandrasekaran, R. Y., Hou, X., Troutman, M. D., Verhoest, P. R., Villalobos, A., and Will, Y. (2010) Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes. ACS Chem. Neurosci. 1, 420−434. (2) Wager, T. T., Hou, X., Verhoest, P. R., and Villalobos, A. (2010) Moving beyond rules: The development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem. Neurosci. 1, 435−449. (3) Ghose, A. K., Ott, G. R., and Hudkins, R. L. (2016) Technically Extended MultiParameter Optimization (TEMPO): AnAdvanced Robust Scoring Scheme To Calculate Central Nervous System Druggability and Monitor Lead Optimization. ACS Chem. Neurosci., DOI: 10.1021/acschemneuro.6b00273. (4) Damijonaitis, A., Broichhagen, J., Urushima, T., Hüll, K., Nagpal, J., Laprell, L., Schönberger, M., Woodmansee, D. H., Rafiq, A., Sumser, M. P., Kummer, W., Gottschalk, A., and Trauner, D. (2015) AzoCholine Enables Optical Control of Alpha 7 Nicotinic Acetylcholine Receptors in Neural Networks. ACS Chem. Neurosci. 6, 701−707. (5) Schoenberger, M., Damijonaitis, A., Zhang, Z., Nagel, D., and Trauner, D. (2014) Development of a New Photochromic Ion Channel Blocker via Azologization of Fomocaine. ACS Chem. Neurosci. 5, 514−518. (6) Lensing, C. J., Adank, D. N., Doering, S. R., Wilber, S. L., Andreasen, A., Schaub, J. W., Xiang, Z., and Haskell-Luevano, C. (2016) Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, a 250-Fold Selective Melanocortin-4 Receptor (MC4R) Antagonist over the Melanocortin-3 Receptor (MC3R), Affects Energy Homeostasis in Male and Female Mice Differently. ACS Chem. Neurosci. 7, 1283−1291. (7) Bevins, R. A., and Charntikov, S. (2015) We Know Very Little about the Subjective Effects of Drugs in Females. ACS Chem. Neurosci. 6, 359−361. (8) SAMHSA. (2014) Substance Abuse Mental Health Services Administration, Results from the 2013 National Survey on Drug Use and Health: Summary of National Findings, Substance Abuse Mental Health Services Administration, Rockville, MD. (9) Compton, W. M., Jones, C. M., and Baldwin, G. T. (2016) Relationship between Nonmedical Prescription-Opioid Use and Heroin Use. N. Engl. J. Med. 374, 154−63. (10) Lebois, E. P., Trimper, J. B., Hu, C., Levey, A. I., and Manns, J. R. (2016) Effects of Selective M1Muscarinic Receptor Activation on Hippocampal Spatial Representations and Neuronal Oscillations. ACS Chem. Neurosci. 7, 1393−1405. (11) Islam, R., Zhang, Y., Xu, L., Sah, P., and Lynch, J. W. (2016) A Chemogenetic Receptor That Enhances the Magnitude and Frequency of Glycinergic Inhibitory Postsynaptic Currents without Inducing a Tonic Chloride Flux. ACS Chem. Neurosci., DOI: 10.1021/acschemneuro.6b00382.
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DOI: 10.1021/acschemneuro.6b00461 ACS Chem. Neurosci. 2017, 8, 1−3
