Chemistry and Neuroscience
We use organic synthesis and molecular design to address exciting problems in neuroscience and brain medicine. The main theme in our research group is to develop new methods for both the imaging and repair of synapses in the brain. We use the entire spectrum of molecular space (small organic molecules, proteins, polymers, nanomaterials), develop in vitro and in vivo assays, and partner with neurobiologists, neuropharmacologists, and clinicians to take on a range of projects.
Organic synthesis is one of the core lines of expertise in our group. We have formulated and documented the key concepts of C-H bond functionalization as a new and general approach to chemical assembly of complex organic compounds and materials (“C-H bonds as ubiquitous functionality”) and developed a number of new chemical transformations. We also formulated the two major consequences of C-H bond functionalization: 1) Novel strategic opportunities for construction of carbon skeletons, and 2) Complex core diversification or late stage functionalization, both now widely pursued in both academia and industry. We apply this approach to the design and synthesis of imaging agents, biological probes, and experimental therapeutics (see Synaptic Imaging, Chemical Biology, and Experimental Therapeutics). We also develop new reactions in the context of specific projects (e.g., synthesis of brain receptor modulators or direct chemical synthesis of drug metabolites via C-H bond oxidation). We draw inspiration from complex natural products, leads identified via high throughput screening of diverse chemical libraries, and exciting nanomaterials (as sensors or delivery vehicles).
We have developed a new class of imaging agents (in collaboration with Prof. David Sulzer, Departments of Psychiatry, Neurology and Pharmacology) termed “Fluorescent False Neurotransmitters” (FFNs) that act as fluorescent tracers of neurotransmitters. FFNs provide the first means for optical imaging (via multiphoton microscopy) of neurotransmitter release at discreet presynaptic terminals in the brain. We are developing both ex vivo and in vivo imaging methods in rodents, and study the synaptic release properties of our imaging agents in both normal and pathological states. We are also interested in using FFNs and other imaging probes to provide the ability to study the effects of pharmacological agents on synaptic activity. This work spans a wide range of approaches including organic synthesis, molecular design, viral delivery of sensors, optogenetics, and in vivo microscopy. We are developing a number of experimental platforms for discovery and development of novel imaging probes. We aim to develop chemical imaging agents and biomarker probes that may enable imaging in different modalities (e.g., optical, PET) and that may also be applicable to humans.
Chemical Biology and Experimental Therapeutics
We study natural products with interesting neurobiological activities. In this context we develop robust synthetic approaches to enable not only the synthesis of the natural products themselves but also complete mapping of the structural space of these compounds. We then study their receptor modulation and signaling activity in living cells (transfected cell lines, primary neurons), animal disease models and develop the required quantitative assays (e.g. for quantitation of kinase signaling pathways). We also study drugs with established clinical efficacy but unknown molecular mechanisms. We are particularly interested in chemical entities that can stimulate synaptic and or circuit repair, neuro- and synaptogenesis. The important central idea is to enable both the repair and imaging of synaptic function in the brain.
Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States”
Vaclav Havel, Andrew C. Kruegel, Benjamin Bechand, Scot McIntosh, Leia Stallings, Alana Hodges, Madalee G. Wulf, Melissa Nelson, Amanda Hunkele, Mike Ansonoff, John E. Pintar, Christopher Hwu, Najah Abi-Gerges, Saheem A. Zaidi, Vsevolod Katritch, Mu Yang, Jonathan A. Javitch, Susruta Majumdar, Scott E. Hemby, Dalibor Sames
BioRxiv 2021, https://www.biorxiv.org/content/10.1101/2021.07.22.453441v1
“Site Selective C-H Functionalization of Mitragyna Alkaloids Reveals a Molecular Switch for Tuning Opioid Receptor Signaling Efficacy”
Srijita Bhowmik, Juraj Galeta, Václav Havel, Melissa Nelson, Abdelfattah Faouzi, Benjamin Bechand, Tomas Fiala, Amanda Hunkele, Andrew Kruegel, Susruta Majumdar, Jonathan A. Javitch, Dalibor Sames
Nature Commun. 2021, 12, 3858.
“Chemical Targeting of Voltage Sensitive Dyes to Specific Cells and Molecules in the Brain”.
Tomas Fiala, Jihang Wang, Matthew Dunn, Peter Šebej, Se Joon Choi, Ekeoma C. Nwadibia, Eva Fialova, Diana M. Martinez, Claire E. Cheetham, Keri J. Fogle, Michael J. Palladino, Zachary Freyberg, David Sulzer, and Dalibor Sames
Journal of the American Chemical Society 2020, 142, 9285-9301.
“A Single Administration of the Atypical Psychedelic Ibogaine or its Metabolite Noribogaine Induces an Antidepressant-like Effect in Rats”
Paola Rodríguez, Jessika Urbanavicius, José Pedro Prieto, Sara Fabius, Ana Laura Reyes, Václav Havel, Dalibor Sames, Cecilia Scorza, and Ignacio Carrera.
ACS Chemical Neuroscience 2020, 11, 1661-1672.
“7-hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of its Analgesic Effect”.
Kruegel, A.C; Uprety, R.; Grinnell, S.G.; Langreck, C.; Pekarskaya, E. A.; Le Rouzic, V.; Ansonoff, M.; Gassaway, M. M.; Pintar, J. E.; Pasternak, G. W.; Majumdar, S.; Javitch J. A.; Sames, D.
ACS Central Science 2019, 5, 992-1001. doi.org/10.1021/acscentsci.9b00141
“Ibogaine Modifies GDNF, BDNF and NGF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits.” Soledad Marton, Bruno Gonzalez, Sebastian Rodriguez, Ernesto Miquel, Laura Martinez Palma, Mariana Pazos, Jose Pedro Prieto, Paola Rodriguez, Dalibor Sames, Gustavo Seoane, Cecilia Scorza, Patricia Cassina, and Ignacio Carrera. ChemRxiv (Preprint) 2018
“Chemical Targeting of Voltage Sensitive Dyes to Specific Cell Types in the Brain.”
Tomas Fiala, Jihang Wang, Matthew Dunn, Peter Sebej, Ekeoma Nwadibia, Diana M. Martinez, Claire E. Cheetham, Keri J. Fogle, Michael J. Palladino, Yuki Bando, Rafael Yuste, Zachary Freyberg, David Sulzer, and Dalibor Sames. ChemRxiv (Preprint) 2018
“Design of a Norepinephrine Optical Tracer for Imaging Individual Noradrenergic Synapses and Their Activity in vivo”. Matthew Dunn, Adam Henke, Samuel Clark, Yekaterina Kovalyova, Kimberly A. Kempadoo, Richard J. Karpowicz, Jr., Eric R. Kandel, David Sulzer, Dalibor Sames. Nature Commun. 2018, 9, 2838.
“Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons”. Adam Henke, Yekaterina Kovalyova, Matthew Dunn, Niko G. Gubernator, Iva Dincheva, Dominik Dreier, Christopher Hwu, Mark S. Ansorge, David Sulzer, Dalibor Sames. ACS. Chem. Neurosci. 2018, DOI: 10.1021/acschemneuro.7b00320.
“ Identification of fluorescent small molecule compounds for synaptic labeling by image-based, high-content screening”. Matthew Dunn, Umed Boltaev, Anne Beskow, Sergey Pampou, Ronald Realubit, Torcato Meira, Joao Vaz Silva, Rose Reeb, Charles Karan, Steffan Jockusch, David Sulzer, Young Tae Chang, Dalibor Sames, Clarissa Waites. ACS. Chem. Neurosci. 2018, DOI: 10.1021/acschemneuro.7b00263.
“Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists”. Umed Boltaev, Yves Meyer, Farangis Tolibzoda, Teresa Jacques, Madalee Gassaway, Qihong Xu, Florence Wagner, Yan-Ling Zhang, Michelle Palmer, Edward Holson, and Dalibor Sames. Science Signal. 2017, 10, eaal1670.
“Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT”. Jenny I. Aguilar, Matthew Dunn, Susana Mingote, Caline S. Karam, Zachary J. Farino, Mark S. Sonders, Se Joon Choi, Anna Grygoruk, Yuchao Zhang, Carolina Cela, Ben Jiwon Choi, Jorge Flores, Robin J. Freyberg, Brian D. McCabe, Eugene V. Mosharov, David E. Krantz, Jonathan A. Javitch, David Sulzer, Dalibor Sames, Stephen Rayport, and Zachary Freyberg. Neuron 2017, 95, 1074–1088. https://doi.org/10.1016/j.neuron.2017.07.038
“The Behavioral Effects of the Antidepressant Tianeptine Require the Mu Opioid Receptor”. Benjamin A. Samuels, Katherine M. Nautiyal, Andrew C Kruegel, Marjorie R. Levinstein, Valerie M Magalong, Madalee M Gassaway, Steven G Grinnell, Jaena Han, Michael A Ansonoff, John E Pintar, Jonathan A Javitch, Dalibor Sames and René Hen. Neuropsychopharmacol. 2017, 42, 2052-2063. doi: 10.1038/npp.2017.60
“Accessing Drug Metabolites via Transition-Metal Catalyzed C-H Oxidation: Liver as Synthetic Inspiration”. Julien Genovino, Dalibor Sames, Lawrence G. Hamann, and B. Barry Toure. Angew. Chem. Int. Ed. 2016, 55, 14218-14238.
“Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators”. Kruegel, A.C; Gassaway, M. M.; Kapoor, A.; Varadi, A.; Majumdar, S.; Filizola, M.; Javitch J. A.; Sames, D. Am. Chem. Soc. 2016, 138, 6754-64. doi: 10.1021/jacs.6b00360
“Fluorescent false neurotransmitter reveals functionally silent dopamine vesicle clusters in the striatum.” Daniela B. Pereira, Yvonne Schmitz, Jozsef Meszaros, Paolimi Merchant, Gang Hu, Shu Li, Adam Henke, Jose E. Lizardi-Ortiz, Richard J. Karpowicz Jr, Travis J. Morgenstern, Mark S. Sonders, Ellen Kanter, Pamela C. Rodriguez, Eugene V. Mosharov, Dalibor Sames & David Sulzer. Nature Neuroscience 2016, 19, 578-586. doi:10.1038/nn.4252
“Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain,” Zachary Freyberg, Mark S. Sonders, Jenny I. Aguilar, Takato Hiranita, Caline S. Karam, Jorge Flores, Andrea B. Pizzo, Yuchao Zhang, Zachary J. Farino, Audrey Chen, Ciara A. Martin, Theresa A. Kopajtic, Hao Fei, Gang Hu, Yi-Ying Lin, Eugene V. Mosharov, Brian D. McCabe, Robin Freyberg, Kandatege Wimalasena, Ling-Wei Hsin, Dalibor Sames, David E. Krantz, David Sulzer, Jonathan A. Javitch. Nature Communications 2016, 7, doi:10.1038/ncomms10652
“Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound.” Madalee M. Gassaway, Teresa L. Jacques, Andrew C. Kruegel, Richard J. Karpowicz Jr., Xiaoguang Li, Shu Li, Yves Myer, and Dalibor Sames. ACS Chemical Biology 2016, 11, 77-87.
“Synaptic optical imaging platforms: Examining pharmacological modulation of neurotransmitter release at discrete synapses. Paolomi Merchant, David Sulzer, Dalibor Sames. Neuropharmacology. 2015, 98, 90-94
“Constructing Iboga Alkaloids via C-H Bond Functionalization: Examination of the Direct and Catalytic Union of Heterarenes and Isoquinuclidine Alkenes,” J. Org. Chem. 2015, 80, 2062-2071.
“NeuO: A Fluorescent Chemical Probe for Live Neuron Labeling,” Er, J. C.; Leong, C.; Teoh, C. L.; Yuan, Q.; Merchant, P.; Dunn, M.; Sulzer, D.; Sames, D.; Bhinge, A.; Kim, D.l Kim, S.-M.; Yoon, M.-H.; Stanton, L. W.; Je, S. H.; Yun, S.-W.; Chang, Y.-T. Angew. Chem. Int. Ed. 2015, 54, 2442-2446.
“Access to Drug Metabolites via C-H functionalization: copper-catalyzed aerobic oxidation of N,N-dimethylalkylamines in comples pharmaceuticals,” Genovino, J., Sames, D., Touré, B. Tet. Lett. 2014, doi:10.1016/j.tetlet.2014.11.037
“The Atypical Antidepressant and Neurorestorative Agent Tianeptine is a mu-Opioid Receptor Agonist,” Gassaway, M. M.; Rives, M.-L.; Kruegel, A.C; Javitch, J. A.; Sames, D. Transl. Psych. 2014, 4, 1-5.
“Paradoxical Abatement of Striatal Dopaminergic Transmission by Cocaine and Methylphenidate” Federici, M.; Latagliata, E.C.; Ledonne A.; Rizzo F.R.; Feligioni M.; Sulzer, D.; Dunn, M.; Sames, D.; Gu, H.; Nisticò, R.; Puglisi-Allegra, S., Mercuri, N.B. J. Biol. Chem. 2014, 289, 264-274.
“Complementation of Biotransformations with Chemical C–H Oxidation: Copper-Catalyzed Oxidation of Tertiary Amines in Complex Pharmaceuticals,” Genovino, J., Lütz, S., Sames, D., Touré, B. J. Am. Chem. Soc. 2013, 135, 12346-12352.
“Intermolecular Energy Transfer from Tb3+ to Eu3+ in Aqueous Aggregates and on the Surface of Human Cells”. Minhee Lee, Matthew S. Tremblay, Steffen Jockusch, Nicholas J. Turro, and Dalibor Sames. ACS Org. Lett. 2011, ASAP
“Fluorescent False Neurotransmitters Visualize Dopamine Release from Individual Presynaptic Terminals,” Niko G. Gubernator, Hui Zhang, Roland G. W. Staal, Eugene V. Mosharov, Daniela Pereira, Minerva Yue, Vojtech Balsanek, Paul A. Vadola, Bipasha Mukherjee, Robert H. Edwards, David Sulzer, and Dalibor Sames, Science, Science Express (2009)
“C-H Bonds as Ubiquitous Functionality: A General Approach to Complex Arylated Pyrazoles via Sequential Regioselective C-Arylation and N-Alkylation Enabled by SEM-Group Transposition,” Roman Goikhman, Teresa L. Jacques, and Dalibor Sames, J. Am. Chem. Soc. 131, 3042-3048 (2009)
“C-H Bond Functionalization via Hydride Transfer: Lewis Acid Catalyzed Alkylation Reactions by Direct Intramolecular Coupling of sp3 C-H Bonds and Reactive Alkenyl Oxocarbenium Intermediates,” Kevin M. McQuaid and Dalibor Sames, J. Am. Chem. Soc. 131, 402-403 (2009)
“Imaging Induction of Cytoprotective Enzymes in Intact Human Cells: Coumberone, a Metabolic Reporter for Human AKR1C Enzymes Reveals Activation by Panaxytriol, an Active Component of Red Ginseng,” Marlin Halim, Dominic J. Yee, and Dalibor Sames, J. Am. Chem. Soc. 130, 14123-14128 (2008)
“A Luminescent Sensor for Tyrosine Phosphorylation,” Matthew S. Tremblay, Minhee Lee, and Dalibor Sames, Org. Lett. 10, 5-8 (2008)
“Harnessing Functional Plasticity of Enzymes: A Fluorogenic Probe for Imaging 17ß-HSD10 Dehydrogenase, an Enzyme Involved in Alzheimer’s and Parkinson’s Diseases,” Mary K. Froemming and Dalibor Sames, J. Am. Chem. Soc. 129, 14518-14522 (2007)
“Ruthenium Catalyzed Decarbonylative Arylation at sp3 Carbon Centers in Pyrrolidine and Piperidine Heterocycles,” Denis V. Gribkov, Stefan J. Pastine, Michael Schnurch, and Dalibor Sames, J. Am. Chem. Soc. 129, 11750-11755 (2007)
“Transposing Molecular Fluorescent Switches into the Near-IR: Development of Luminogenic Reporter Substrates for Redox Metabolism,” Marlin Halim, Matthew S. Tremblay, Steffen Jockusch, Nicholas J. Turro, and Dalibor Sames, J. Am. Chem. Soc. 129, 7704-7705 (2007)
“Cocktails of Tb3+ and Eu3+ Complexes: A General Platform for the Design of Ratiometric Optical Probes,” Matthew S. Tremblay, Marlin Halim, and Dalibor Sames, J. Am. Chem. Soc. 129, 7570-7577 (2007)
“Two-Photon Excitation of Fluorogenic Probes for Redox Metabolism: Dramatic Enhancement of Optical Contrast Ratio by Two-Photon Excitation,” Steffen Jockusch, Qingdong Zheng, Guang S. He, Haridas E. Pudavar, Dominic J. Yee, Vojtech Balsanek, Marlin Halim, Dalibor Sames, Paras N. Prasad, and Nicholas J. Turro, J. Phys. Chem. C 111, 8872-8877 (2007)