Basic Research

Southern Research scientists are currently engaged in the following basic research initiatives in CNS/neurological diseases:

Neuroprotective Agents and Antiglioma Agents, Maurizio Grimaldi, M.D., Ph.D.

The overall focus of Dr. Grimaldi's research is to understand brain cell physiology and how it relates to models of brain disease for the purpose of designing potential therapeutic agents that can reverse changes induced by specific pathologic conditions. On a regular basis, the neuropharmacology/neuroscience laboratory prepares brain cells, including astrocytes and neurons, which are the primary sources of data. The laboratory also maintains and stores several cell lines of glial, neuronal, and muscular origin, both animal and human, to validate data obtained in primary cells. This repertoire of cells is used to achieve the objectives stated above.

The neuropharmacology lab is equipped with a state-of-the-art high-speed, high-resolution imaging system that allows performing experiments to execute live monitoring of fluorescent dyes inside single brain cells in culture using ratiometric and non-ratiometric florescent probes. The laboratory investigates the properties of the refilling of intracellular calcium stores in terms of functioning, macromolecular organization, and regulation. Also, the ion channel that is involved in the entry of calcium from the extracellular space upon depletion of the intracellular calcium stores is not yet identified and characterized. One of the main goals of Dr. Grimaldi's lab is to identify the ion channel, to design novel drugs that can modulate it, and to determine if this channel could be involved in pathological conditions.

A primary focus of Dr. Grimaldi's research is the identification of novel therapeutic agents with neuroprotective activity. Using in vitro models of neurodegenerative disorders, the signal transduction chain that is involved in neuronal cell death is investigated. A unique pharmacological approach is used to design and test possible therapeutic agents. In collaboration with other scientists at Southern Research, the effects of thousands of compounds are evaluated using high-throughput and high-content screening. The compounds identified are returned to the lab in order to characterize their mechanism of action and begin animal testing to determine pharmacokinetic properties and efficacy.

Dr. Grimaldi is also engaged in neurooncology research with a specific interest in the mechanisms of transformation of glial cells. In particular, significant differences in calcium homeostasis between normal astrocytes and cancerous glial cells have been identified. Dr. Grimaldi's laboratory investigates the meaning of such differences in terms of glial cells' proliferation and transformation. Also, the effects of agents able to affect the involved system are evaluated on transformation and proliferation of glial cells. Dr. Grimaldi attempts to adopt these models to high-throughput screening in order to evaluate a possible role as antiproliferating agents, among the thousands of compounds present in the Southern Research compound library.

Basic Research in NCS Proteins and Drug Discovery, Karl-Heinz Braunewell, Ph.D.

Calcium signaling. Calcium plays a key role in cellular signaling processes such as regulation of enzymatic activities and neurotransmitter release, neuronal plasticity, and gene expression. Calcium-binding proteins have an important role as mediators of calcium signals in cellular signaling pathways in physiological as well as in pathophysiological processes of the central nervous system. The investigation of intracellular neuronal calcium sensor (NCS) proteins, such as VILIP-1, -2, -3, and hippocalcin, neurocalcin, and NCS-1 may reveal new insights into the physiology and pathophysiology of calcium signaling processes in the brain. (For review, see Braunewell 2006 TiPS. 26:345-351.)

The general goal in Dr. Braunewell's research lab is to understand calcium-dependent signaling mechanisms at the molecular and cellular level, as well as to clarify the role of calcium-dependent signaling in disease. To reach this goal, a broad interdisciplinary approach including biochemical, molecular biology, cell culture, immunohistochemcial as well as electrophysiological methods are employed, and various collaborations with national and international colleagues have been established.

Drug Discovery. The future goal will be to study the function of NCS proteins in synaptic plasticity and in neurological and psychiatric disorders, ranging from Alzheimer's disease to schizophrenia. An interesting facet is the role of NCS proteins for invasiveness of brain tumors. At Southern Research, Dr. Braunewell is actively involved in drug discovery for targets in brain cancers and several CNS disorders including Alzheimer's disease, addiction, pain, depression, and schizophrenia.

Drug Design and Synthetic Medicinal Chemistry, Sam Ananthan, Ph.D.

Drug design and medicinal chemistry efforts span a range of targets, including G-protein coupled receptors (GPCRs), ion channels, and neurotransmitter transporters of the central nervous system. A current research focus involves the design, synthesis, and development of opioid ligands as novel analgesic agents. The pursuit of these efforts is based on emerging evidence indicating that compounds possessing mixed mu agonist/delta antagonist activities are likely to display analgesic activity devoid of tolerance, dependence, and gastrointestinal side effects. The design of novel ligands with these dual interaction profiles is guided by structure-based drug design strategies using homology models of the target receptors and by predictive 3D-QSAR (CoMFA) models developed using functional acidity data on a series of ligands possessing a morphinan scaffold.

In another project, drug design and synthetic efforts are directed toward the design and synthesis of antagonist or partial agonist ligands with high selectivity for dopamine D3 subtype of receptors. Rational drug design approaches using homology-based models of the dopamine D3 and D2 dopamine receptors are currently being explored to design compounds with improved binding affinity and selectivity toward the D3 subtype of receptors.

Also being pursued are efforts directed toward lead discovery and optimization of allosteric modulators of biogenic amine transporters (dopamine transporter, norepinephrine transporter and 5-hydroxytryptamine transporter) with the potential for therapeutic application in several CNS disorders, including addiction.