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July 2021 New publication on novel class of psychedelic Iboga alkaloids. Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities. Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, currently approved medications do not reverse the persistent neurocircuitry and psychological changes that underlie addiction states, highlighting an urgent need for radically different therapeutic approaches. Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt maladaptive habits including opioid use in drug-dependent humans. However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias. We introduce a new class of iboga alkaloids - "oxa-iboga" - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in addiction models and no cardiac pro-arrhythmic potential, compared to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine intake after a single dose in rat models of addiction and persistent reduction of morphine intake after a short treatment regimen. Oxa-noribogaine maintains and enhances the ability of iboga compounds to effect lasting alteration of addiction-like states while addressing iboga's cardiac liability. As such, oxa-iboga compounds represent candidates for a new kind of anti-addiction pharmacotherapeutics. Read about our exciting work in BioRxiv. [html] [pdf]
June 2021 New publication describing a systematic examination of late stage functionalization of kratom alkaloids, which provided efficient access to novel C11-mitragynine analogs and identified 11-F-7OH as an important lead compound for further investigations. Mitragynine is the most abundant alkaloid component of the psychoactive plant material "kratom", which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We developed a new synthetic method for selective functionalization of the unexplored C11 position of the mitragynine scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. We discovered that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. In the 7-hydroxymitragynine (7OH) series, the high efficacy parent compound was transformed to an equipotent low efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests after systemic administration. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects. Read about our exciting work in Nat. Commun. [html] [pdf]
May 2020 Our lab has developed the first completely non-genetic platform for targeting voltage sensitive dyes to specific neuronal cells and their axons in live brain tissue and achieved functional voltage imaging with probes targeted to only natively-expressed protein targets. Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. The impact of these highly lipophilic sensors has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a nongenetic molecular platform for cell- and molecule-specific targeting of synthetic VSDs in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of VSDs by dynamic encapsulation and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology. Read about our exciting work in J. Am. Chem. Soc. [html] [pdf]
May 2020 Tom Fiala (senior graduate student) receives two prestigious postdoctoral scholarships:
  • Marie Curie Individual Fellowship (2-year fellowship from the European Union)
  • Swiss Government Excellence Scholarship (1-year fellowship from the Swiss Government)
  • Apr. 2020 Congratulations to Christopher Hwu (1st year grad student) for receiving the Jack Miller Teaching Award and as the Finalsit for the prestigious Presidential Teaching Award!
    Apr. 2020 Our paper on kratom's mechanism of action (ACS Central Science paper on 7-hydroxymitragynine as an active metabolite) is featured in Nora Volkow's review of NIDA's 2019 achievements, see the Basic Research section.
    Apr. 2020 New publication on antidepressant effects of ibogaine and noribogaine in rats. Anecdotal reports and open label case studies in humans indicated that the psychedelic alkaloid ibogaine exert profound anti-addictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite noribogaine, in substance use disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose and time-dependence) induced by the acute ibogaine and noribogaine (20 and 40 mg/kg, i.p.) administration in rats using the forced swim test (FST). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine's FST effect was short lived (30 minutes) and correlated with high brain concentrations (estimated > 8 mM of free drug), while the ibogaine's antidepressant-like effect was significant at 3 hours. At this time point, both ibogaine and noribogaine were present in rat brain, at concentrations which cannot produce the same behavioral outcome on their own (ibogaine ~ 0.5 mM, noribogaine ~ 2.4 mM). Our data suggest a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine. Read about our exciting work in ACS Chem. Neurosci. [html] [pdf]
    May 2019 7-hydroxymitragynine is an active metabolite of kratom psychoactive plant. Mitragynina speciosa, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine, and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans. Read about our exciting work in ACS Cent. Sci., also featured in ACS Weekly Press, ACS Cent. Sci. First Reactions, and Nora Volkow's review of NIDA's 2019 achievements. [html] [pdf]
    Apr. 2019 Congratulations to Benjamin Bechand (2nd year grad student) for receiving the Jack Miller Teaching Award and the prestigous Presidential Teaching Award!
    Mar. 2019 Ibogaine induces expression of neuroplasticity factors GDNF and BDNF. Congratulations to Nacho and Dali! Nacho (Dr. Ignacio Carrera) was a former Postdoctoral Scientist in the Sames lab, now an Assistant Professor at Universidad de la Republica, Montevideo in Uruguay. This study shows that the psychedelic alkaloid ibogaine, known to disrupt drug addiction and dependence, elevates the expression of several growth factors/neurotrophins in the rat brain, including the glial cell line derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), and nerve growth factor (NGF). Nacho's study confirmed the previous finding by Dr. Ron's laboratory, which demonstrated the ibogaine-GDNF connection, and extended it by examining additional growth factors in several brain areas. The GDNF hypothesis of ibogaine's long lasting anti-addition effects is one of the key inspirations for our active study in synaptic restoration and neurotherapeutics development (for example, see M. M. Gassaway et al., 2015, Deconstructing the Iboga Alkaloid Skeleton). Read about our exciting work in Front. Pharmacol. [html] [pdf]
    Dec. 2018 Dopamine neurotransmission is suspected to play important physiological roles in multiple sparsely innervated brain nuclei, but there has not been a means to measure synaptic dopamine release in such regions. The globus pallidus externa (GPe) is a major locus in the basal ganglia that displays a sparse innervation of en passant dopamine axonal fibers. Due to the low levels of innervation that preclude electrochemical analysis, it is unknown if these axons engage in neurotransmission. To address this, we introduce an optical approach using a pH-sensitive fluorescent false neurotransmitter, FFN102, that exhibits increased fluorescence upon exocytosis from the acidic synaptic vesicle to the neutral extracellular milieu. In marked contrast to the striatum, FFN102 transients in the mouse GPe were spatially heterogeneous and smaller than in striatum with the exception of sparse hot spots. GPe transients were also significantly enhanced by high frequency stimulation. Our results support hot spots of dopamine release from substantia nigra axons. Read about our exciting work in eLife. [html] [pdf]
    July 2018 Norepinephrine is a monoamine neurotransmitter with a wide repertoire of physiological roles in the peripheral and central nervous systems. There are, however, no experimental means to study functional properties of individual noradrenergic synapses in the brain. Development of new approaches for imaging synaptic neurotransmission is of fundamental importance to study specific synaptic changes that occur during learning, behavior, and pathological processes. Here, we introduce fluorescent false neurotransmitter 270 (FFN270), a fluorescent tracer of norepinephrine. As a fluorescent substrate of the norepinephrine and vesicular monoamine transporters, FFN270 labels noradrenergic neurons and their synaptic vesicles, and enables imaging synaptic vesicle content release from specific axonal sites in living rodents. Combining FFN270 imaging and optogenetic stimulation, we find heterogeneous release properties of noradrenergic synapses in the somatosensory cortex, including low and high releasing populations. Through systemic amphetamine administration, we observe rapid release of cortical noradrenergic vesicular content, providing insight into the drug's effect. Read about our exciting work in Nature Communications. [html] [pdf]
    Feb. 2018 Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure-activity study revealed the basic structural chemotype of aminoalkyl acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SERT inhibitors in 96-well cell culture assays, as well as specific labeling of serotonergic neurons of the dorsal raphe nucleus in the living tissue of acute mouse brain slices. While we found only minor FFN246 accumulation in serotonergic axons in murine brain tissue, FFN246 effectively traces serotonin uptake and packaging in the soma of serotonergic neurons with improved photophysical properties and loading parameters compared to known serotonin-based fluorescent tracers. Read about our exciting work in ACS Chem. Neurosci. [html] [pdf]
    Feb. 2018 Few tools are available for noninvasive imaging of synapses in the living mammalian brain. Current paradigms require the use of genetically modified mice or viral delivery of genetic material to the brain. To develop an alternative chemical approach, utilizing the recognition of synaptic components by organic small molecules, we designed an imaging-based, high-content screen in cultured cortical neurons to identify molecules based on their colocalization with fluorescently tagged synaptic proteins. We used this approach to screen a library of ~7000 novel fluorescent dyes, and identified a series of compounds in the xanthone family that exhibited consistent synaptic labeling. Follow-up studies with one of these compounds, CX-G3, demonstrated its ability to label acidic organelles and in particular synaptic vesicles at glutamatergic synapses in cultured neurons and murine brain tissue, indicating the potential of this screening approach to identify promising lead compounds for use as synaptic markers, sensors, and targeting devices. Read about our exciting work in ACS Chem. Neurosci. [html] [pdf]
    Aug. 2017 Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), have emerged as key regulators of brain plasticity and represent disease-modifying targets for several brain disorders, including Alzheimer's disease and major depressive disorder. Because of poor pharmacokinetic properties of BDNF, the interest in small-molecule TrkB agonists and modulators is high. Several compounds have been reported to act as TrkB agonists, and their increasing use in various nervous system disorder models creates the perception that these are reliable probes. To examine key pharmacological parameters of these compounds in detail, we have developed and optimized a series of complementary quantitative assays that measure TrkB receptor activation, TrkB-dependent downstream signaling, and gene expression in different cellular contexts. Although BDNF and other neurotrophic factors elicited robust and dose-dependent receptor activation and downstream signaling, we were unable to reproduce these activities using the reported small-molecule TrkB agonists. Our findings indicate that experimental results obtained with these compounds must be carefully interpreted and highlight the challenge of developing reliable pharmacological activators of this key molecular target. Read about our exciting work in Science Signaling. [html] [pdf]
    Aug. 2017 The ability of presynaptic dopamine terminals to tune neurotransmitter release to meet the demands of neuronal activity is critical to neurotransmission. Although vesicle content has been assumed to be static, in vitro data increasingly suggest that cell activity modulates vesicle content. Here, we use a coordinated genetic, pharmacological, and imaging approach in Drosophila to study the presynaptic machinery responsible for these vesicular processes in vivo. We show that cell depolarization increases synaptic vesicle dopamine content prior to release via vesicular hyperacidification. This depolarization-induced hyperacidification is mediated by the vesicular glutamate transporter (VGLUT). Remarkably, both depolarization-induced dopamine vesicle hyperacidification and its dependence on VGLUT2 are seen in ventral midbrain dopamine neurons in the mouse. Together, these data suggest that in response to depolarization, dopamine vesicles utilize a cascade of vesicular transporters to dynamically increase the vesicular pH gradient, thereby increasing dopamine vesicle content. Read about our exciting work in Neuron. [html] [pdf]
    Apr. 2017 Congratulations to Tomas Fiala (2nd year grad student) for receiving the Jack Miller Teaching Award!
    Mar. 2017 Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors, are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously unknown mechanism of action. We recently reported that tianeptine is a full agonist at the mu opioid receptor (MOR). Here we demonstrate that the acute and chronic antidepressant-like behavioral effects of tianeptine in mice require MOR. Interestingly, while tianeptine also produces many opiate-like behavioral effects such as analgesia and reward, it does not lead to tolerance or withdrawal. Furthermore, the primary metabolite of tianeptine (MC5), which has a longer half-life, mimics the behavioral effects of tianeptine in a MOR-dependent fashion. These results point to the possibility that MOR and its downstream signaling cascades may be novel targets for antidepressant drug development. Read about our exciting work in Neuropsychopharmacology. [html] [pdf]
    Feb. 2017 The Sames group would like to officially welcome Srijita Bhowmik to the group as a new graduate student!
    Oct. 2016 Can classical and modern chemical C-H oxidation reactions complement biotransformation in the synthesis of drug metabolites? We have surveyed the literature in an effort to try to answer this important question of major practical significance in the pharmaceutical industry. Drug metabolites are required throughout all phases of the drug discovery and development process; however, their synthesis is still an unsolved problem. This Review, not intended to be comprehensive or historical, highlights relevant applications of chemical C-H oxidation reactions, electrochemistry and microfluidic technologies to drug templates in order to access drug metabolites, and also highlights promising reactions to this end. Where possible or appropriate, the contrast with biotransformation is drawn. In doing so, we have tried to identify gaps where they exist in the hope to spur further activity in this very important research area. A review co-written by Dali on the chemical preparation of drug metabolites by transition-metal catalyzed C-H oxidation was published in Angew. Chem. Int. Ed. [html] [pdf]
    June 2016 Our article in JACS about Mitragyna alkaloids function at Mu-opiod receptor made the News of the Week in Chemical & Engineering News!
    May 2016 Though Mu-opiod receptor agonists are used therapeutically for pain management, the use of these agents is often associated with serious side-effects, including addiction and respiratory depression. A class of alkaloids from the Southeast Asian plant Mitragyna speciosa, represented by the prototypical member mitragynine, are an unusual class of opioid receptor modulators with distinct pharmacological properties. In this paper, we describe the first receptor-level functional characterization of mitragynine and related natural alkaloids at the human mu-, kappa-, and delta-opioid receptors. Read about our exciting work in the Journal of the American Chemical Society. [html] [pdf]
    Mar. 2016 Our research, in collaboration with the Sulzer research group, revealing functionally silent dopamine clusters in the striatum has been featured by the Columbia University Medical Center Newsroom! View the press release here.
    Mar. 2016 With the use of fluorescent false neurotransmitter 200 (FFN200), a vesicular monoamine transporter 2 (VMAT2) substrate developed in our lab, we have revealed functionally silent dopamine clusters in the striatum. By monitoring electrically evoked Ca2+ transients with GCaMP3 and FFN200 release simultaneously, we have found that only a small fraction of striatal dopamine axonal sites with uptake-competent VMAT2 vesicles are capable of transmitter release. Read about this exciting work in Nature Neuroscience [html] [pdf]
    Mar. 2016 Until now, the mechanisms of action underlying the ability of amphetamines to elevate extracellular dopamine levels had been suggested but remained unclear. Researchers from Prof. Johnathan Javitch group, in collaboration with our group, have elucidated amphetamine's mechanisms of action using FFN206, a novel fluorescent probe developed in our lab, as well as other novel optical, genetic, and pharmacological approaches. This exciting work not only sheds light on widely-debated mechanisms of amphetamine action specifically, but also demonstrates the utility of FFNs in elucidation of mechanisms of action of CNS drugs, in general. Read about this work in Nature Communications [html] [pdf]
    Feb. 2016 The Sames group would like to officially welcome the following new members to the group:

  • Tomas Fiala - Graduate Student
  • Jihang Wang - Graduate Student
  • Dr. Peter Sebej - Post Doc
  • Dr. Juraj Galeta - Post Doc
  • Welcome!!
    Nov. 2015 Modulation of growth factor signaling pathways presents a new approach to treating neuropsychiatric disorders such as depression. Growth factors and neurotrophins, such as glial cell line-derived neurotrophic growth factor (GDNF) and fibroblast growth factor 2 (FGF2), have been implicated in depression, and enhancement of GDNF has been implicated in the marked reduction of alcohol consumption in rodent addiction models. We have just published a paper on the induction of GDNF release in C6 glioma cells by both XL-008, a novel iboga analog synthesized in our lab and a mixture of FGF2/XL-008. Read about this exciting work in ACS Chemical Biology [html] [pdf]
    Sept. 2015 CONGRATULATIONS to Andrew Kruegel and Matt Dunn on the successful defense of their respective thesis!! Welcome to the family of PhD holders!
    June 2015 Chemical synapses are functional units of the brain that also serve as biomarkers of numerous brain disorders. As such, studying synaptic function at high resolution is essential to understanding the effects of pharmacological agents on synaptic plasticity. We have published an article where we discuss the design and use of fluorescent false neurotransmitters (FFNs), developed in our lab, as an important step in the development of versatile synaptic imaging platforms. Read about our work in Neuropharmacology [html]
    Feb. 2015 We have developed three new intramolecular C-H functionalization procedures that allow access to the core 7-membered ring skeleton ring of iboga alkaloids, a class of natural products with very interesting pharmacology. These cyclizations proved very challenging, though provide practical routes to a diverse iboga analogues. Congratulations to Andrew Kruegel, Souvik Rakshit, Xiaoguang Li, and Dali! Read about our work in JOC [html] [pdf]
    Jan. 2015 In collaboration with Prof. Chang's group, we have contributed to the characterization of NeuO, a novel probe with an unprecedented ability to label and image live neurons selectively over other cells in the brain. This probe addresses existing limitations in live neuron imaging. Check out this exciting body of work in Angew. Chem. Int'l. Ed. [html] [pdf]
    Nov. 2014 Owing to the challenges with scalable access to drug metabolites and their analogs, we have pursued the development of simple C-H oxidations methods allowing access to various structural features found in pharmaceuticals. To this extent, we show that a simple copper-oxygen catalytic system provides a scalable route to complex N-demethylated drug metabolites. Read more of our work in Tetrahedron Lett. [html] [pdf]
    Aug. 2014 Using radioligand binding and cell-based functional assays, we have characterized tianeptine, an atypical antidepressant, as a μ opiod receptor (MOR) agonist. We propose that activation of MOR could be the initial molecular event responsible for triggering many of the known effects of this agent, including its antidepressant actions. Read about our work in Transl. Psychiatry. [html] [pdf]
    June 2014 CONGRATULATIONS to Paolomi Merchant on successfully submitting and defending her dissertation and thesis! Welcome to the family of Ph.D. holders!
    May 2014 Using our false fluorescent neurotransmitters (FFNs), in conjunction with in vitro amperometric and micro dialysis techniques, we showed that cocaine and methylphenidate induce marked depression of synaptic release of dopamine (DA) in mouse striatum. We show that cocaine and methylphenidate can not only increase DA neurotransmission by blocking DA reuptake, as is widely known, but can also block or decrease DA neurotransmission by reducing excocytotic DA release. This biphasic effect on DA neurotransmission could have implications in the observed differential behavioral effects of psychostimulants in treatment of ADHD. Check out our work in J. Biol. Chem. [html] [pdf]
    Oct. 2013 CONGRATULATIONS to Rich Karpowicz on the successful submission and defense of his dissertation and thesis! Welcome to the family of Ph.D. holders!
    July 2013 We have just published a study that represents a first step toward establishing a chemical toolkit (chemotransformations) that can selectively oxidize C-H bonds in complex pharmaceuticals and rapidly deliver drug metabolites. Rapid access to oxidized drugs could facilitate metabolite identification and enable early pharmacology and toxicity studies. Check out our work in JACS. [Abstract] [pdf]
    We have just reported the synthesis and characterization of a new fluorescent probe, FFN206, an excellent VMAT2 substrate capable of detecting VMAT2 activity in intact cells with high selectivity using fluorescence microscopy! We also report the development and validation of a cell-based fluorescence assay amenable to high-throughput screening using VMAT2-transfected HEK cells. Read about this work in ACS Chemical Biology. [Abstract] [pdf]
    May 2013 Congratulations to Richard Karpowicz, Matt Dunn, Dali and our collaborator David Sulzer on their two recently published ACS Chemical Neuroscience articles! In the ACS Chemical Neuroscience Viewpoint article, they discuss recent advancements towards the goal of imaging neurotransmitter secretion in the brain with high spatial resolution; visualization of neurotransmitter release in brain tissue with the spatial resolution of individual synapses; and suggest future directions, challenges, and impact of neurotransmitter imaging on neuroscience.
    In the main article, they discuss the potential use of the fluorescent pyridinium dye APP+, an analogue of the dopaminergic neurotoxin MPP+, as a probe for identifying catecholaminergic innervations in the brain, but not as a candidate for the development of a novel group of FFNs. Check out this work in ACS Chemical Neuroscience! [Abstract] [pdf]
    Feb. 2013 CONGRATULATIONS to Teresa Jacques on successfully submitting her dissertation and defending her thesis! Welcome to the family of Ph.D. holders!
    Jan. 2013 Our recently developed fluorescent false neurotransmitters (FFNs) can be used as optical tracers to visualize neurotransmitter release at individual presynaptic terminals. We describe, here, a pH-responsive FFN probe, FFN102, that enables the optical measurement of individual synaptic terminal activity, as well as evoked release of synaptic vesicle content into the extracellular space, by monitoring fluorescence loss upon vesicle stimulation. This work is published in PNAS [Abstract] [pdf]
    Jan. 2013 We have just published a paper in which we describe a general approach for the synthesis of complex 1,2,4-triazoles via regioselective C-H- bond arylation, and the development of the SEM and THP switch as well as trans-N-alkylation for sequential triazole ring arylation! Check out our work in J. Org. Chem. [Abstract] [pdf]
    Jan. 2013 We would like to welcome our newest member Umed T Boltaev to the group!
    Aug. 2012 One of our recently published articles (J. Org. Chem. ASAP) has been selected by the Editorial Board of SYNFACTS for its important contributions to the field of chemistry! SYNFACTS is a monthly publication aimed at highlighting the most significant recent developments and future trends in synthetic chemistry. Congratulations to Paul, Ignacio, and Dali! You can view the electronic reprint in the SYNFACTS September 2012 issue. [html].
    July 2012 C-H bond functionalization is an active area of research and is very important for the synthesis of organic molecules. Many such reactions, however, suffer from poor compatibility with Lewis basic functional groups, especially amines. We have just reported the development of two mild protocols using PtCl4 or Au(PPh3Cl/AgSbF6 for use with an enhanced substrate scope, as synthetic tools for the structure-activity examination of FFN neuroimaging probes, as well as for the general synthesis of complex coumarins. This work has been published in J. Org. Chem. [Abstract] [pdf]
    June 2012 We have just reported a study of the highly stereoselective intramolecular amination of sp3 C-H bonds via hydride transfer cyclization of N-tosylamines (HT-amination). This work has been published in the Journal of Organic Chemistry as the featured article! Check out our work in J. Org. Chem. ASAP [Abstract] [Full Text]
    Jan. 2012 The Sames group would like to welcome Madalee Gassaway to the group!
    Sep. 2011 We report here a new protocol for highly selective C-H arylation of pyridines containing readily available and synthetically versatile electron-withdrawing substituents. This work expands the scope of catalytic azine functionalization as well as complements existing methods for C-H arylation and Ir-catalyzed borylation of pyridines, and has been published in J. Am. Chem. Soc. [Abstract]
    June 2011 The Sames group welcomes new members:

  • Matthew R. Dunn - Graduate Student
  • Ekeoma C. Nwadibia - Graduate Student
  • Andrew C. Kruegel - Graduate Student
  • Dr. Souvik Rakshit - Post Doc
  • Dr. Yves Meyer - Post Doc
  • Dr. Adam Henke - Post Doc
  • Feb. 2011 Intramolecular energy transfer from carbostyril 124-sensitized Tb3+ to Eu3+ in aqueous aggregates is reported here to show the first example of imaging this phenomenon on the cellular membrane of HEK-293T cells. Our work serves as an example for the applicability of this energy transfer probe for imaging biological systems. Check out our work in Org. Lett. [Abstract]
    Sep. 2010 We describe a novel optical approach for measuring the changes of metabolic fluxes in cells, based on a two-substrate competition between a physiological substrate and a fluorogenic reporter substrate. This work has been published in ACS Chem. Biol. [Abstract]
    July 2010 We developed a general and comprehensive approach for the synthesis of complex aryl imidazoles, where all three C-H bonds of the imidazole core can be arylated in a regioselective and sequential manner. This work has been published as a featured article in J. Org. Chem. [Abstract]
    June 2010 We introduce pH-responsive fluorescent false neurotransmitters (pH-responsive FFNs) as novel probes that act as vesicular monoamine transporter (VMAT) substrates and ratiometric fluorescent pH sensors. This work has been published in J. Am. Chem. Soc. [Abstract]
    Nov. 2009 Our work on fluorescent false neurotransmitters that enabled us to observe neurotransmitter uptake and release from individual presynaptic terminals directly has been published in Journal of Visualized Experiments, a video journal for biological research. Click here to play the video. [html]
    Oct. 2009 The scope of the through-space hydride transfer reactions has been expanded to include terminal alkynes as the hydride acceptors. This work has been published in J. Am. Chem. Soc. [Abstract]
    June 2009 The hydride transfer initiated cyclization of aryl alkyl ethers leads to the formation of dihydrobenzopyrans. Check out our latest work on C-H bond functionalization in Org. Lett. [Abstract] [html] This article has been selected by the Editorial Board of Synfacts. [PDF]
    May 2009 Our study of the nervous system using fluorescent false neurotransmitters has been published in Science. [Abstract] This work has been featured in Chemical & Engineering News. [html] This work has been also reviewed by Nature Methods [html] [pdf] and Physiology [pdf].
    Feb. 2009 The group's latest work on regioselective direct C-arylation of pyrazoles has been published in J. Am. Chem. Soc. [Abstract]
    Jan. 2009 The group's latest work on C-H bond functionalization via hydride transfer has been published in J. Am. Chem. Soc. [Abstract] This article was summarized in Synfacts. [PDF]
    Oct. 2008 The group's latest work on imaging induction of cytoprotective enzymes in intact human cells has appeared in J. Am. Chem. Soc. [Abstact] This article was featured as a "Spotlight" in Chemical Research in Toxicology. [Abstract]
    Aug. 2008 Congratulations to Dali and Professor David Sulzer of the Department of Neuroscience on receiving a 2008-2009 McKnight Foundation Technical Innovations in Neuroscience Award for their project "Development of Fluorescent False Neurotransmitters: Novel Probes for Direct Visualization of Neurotransmitter Release from Individual Presynaptic Terminals."
    Last Updated: Nov. 2015