Our Research Center
CHEMISTRY and NEUROSCIENCE
The Sames research group combines molecular design, organic chemical synthesis, and pharmacology to pursue important and exciting problems in neuroscience and CNS therapeutics development. The main conceptual theme in our research program is to study and develop substances that induce restorative neuroplasticity as a novel class of therapeutics. We also develop new probes and methods for imaging synaptic function in the brain including cell-specific and receptor-specific imaging approaches. We are inspired by psychoactive and psychedelic compounds, and we pursue reverse translation of their clinical effects to preclinical systems where we study their mechanism of action. New mechanistic insights in turn enable a forward translation process of designing and advancing new experimental therapeutics for the treatment of psychiatric and neurological disorders.
Experimental Therapeutics, Basic Science and Drug Development
We search for and study drugs with profound clinical and therapeutic effects but unknown molecular mechanisms. We are particularly interested in chemical entities that can stimulate synaptic, circuit or system-wide restorative neuroplasticity processes. For example, ibogaine and iboga alkaloids continue to serve as an inspiration to our program considering the growing scope of therapeutic effects (interruption of addiction, attenuation of PTSD, and possibly treatment of traumatic brain injury and other neurological disorders). Further, the complex molecular mechanism of ibogaine challenges us to develop novel mechanistic concepts and experimental methods to test them. We elucidated the mechanism of action of Ariadne, a non-hallucinogenic analog in the mescaline class of psychedelics, which was reported to show remarkable signals of therapeutic efficacy (e.g., schizophrenia and Parkinson’s disease). We also discovered the mechanism of tianeptine, a clinically used antidepressant and restorative neuroplastic agent, and described the mechanism of mitragynine, the main alkaloid of the psychoactive plant kratom. We develop robust synthetic approaches to enable complete mapping of the structural space of these compounds. We study receptor modulation and intracellular signaling pathways, use human primary cells where feasible and animal behavior sequencing via machine learning methods, to link the in vitro molecular signaling to in vivo pharmacology and behavior in disease models. We also develop robust neuroplasticity essays in neurons and in vivo.
Synaptic and Brain Receptor Imaging
We have developed a new class of imaging agents termed “Fluorescent False Neurotransmitters” (FFNs) that act as fluorescent tracers of neurotransmitters (in collaboration with Prof. David Sulzer, Departments of Psychiatry, Neurology and Pharmacology). FFNs provided the first means for optical imaging (via multiphoton microscopy) of neurotransmitter release at discreet presynaptic terminals in the brain. FFNs led to a discovery of silent dopamine and norepinephrine synapses in mammalian brain, which are presynaptic boutons that contain synaptic vesicles, accumulate neurotransmitters, but lack the full complement of active zone proteins required for exocytosis. We are developing both ex vivo and in vivo imaging methods in rodents and study the synaptic release properties in normal and pathological states, including co-transmission processes where monoamine synapses release more than one neurotransmitter (for example, co-release of norepinephrine and glutamate, or serotonin and glutamate). We also use FFNs and other imaging probes (neurotransmitter sensors) to study the effects of pharmacological agents on synaptic activity. We have developed a molecular platform for delivery of voltage sensitive dyes to specific neuronal cell types in the brain, using native receptors as anchors. This program is evolving to advance approaches to modulations of receptors in specific cell types and circuits.
Organic Chemical Synthesis
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 numerous 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 these approaches to the design and synthesis of imaging agents, biological probes, and experimental therapeutics. We develop new reactions and synthetic sequences to support the design and SAR studies in specific projects, such as the total synthesis of iboga alkaloids, late-stage C-H functionalization of mitragyna alkaloids, and synthesis of fluorescent receptor tags.