ANANTHAN
LABORATORY

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Research Focus

The major focus of Ananthan Laboratory is to explore the application of ligand-based and structure-based drug design, structure-activity-relationship (SAR) analysis, and multi-parametric lead optimization strategies to develop small molecules suitable for clinical development. Molecular targets of interest include GPCRs, kinases, ion channels, transporters, and protein-protein interactions. Therapeutic areas of special interest include Central nervous System (CNS) disorders (pain, schizophrenia, Parkinson’s disease, anxiety, addiction), cancer, and infectious diseases. His research efforts, particularly in the CNS area, have been continuously funded for more than 25 years by Grants and Contracts from the National Institutes of Health (NIH). Some of the ongoing research projects are:

Mixed function opioid ligands – analgesics with diminished side effects

Opioids such as morphine are the most potent and efficacious agents currently available for the treatment of moderate to severe acute and chronic pain. These drugs primarily act through the mu subtype of the opioid receptors. However, their therapeutic use is limited due to respiratory depression, opioid-induced bowel dysfunction, development of tolerance and dependence, and renewed concerns around addiction liabilities.

There is an urgent unmet medical need for the discovery and development of novel analgesics that are as efficacious as morphine but devoid of significant side effects. Delta receptor gene knockout/knockdown experiments and studies using selective antagonists and bifunctional (mu agonist/delta antagonist) compounds have provided evidence that activation of mu receptor function with simultaneous suppression of delta receptor function produces analgesic effects with greatly diminished mu receptor mediated side effects. Thus, compounds possessing dual but opposing functional activity of mu receptor agonism and delta receptor antagonism have the potential to exhibit broad-spectrum analgesia with a wide safety margin and therapeutic index. Currently, we are engaged in the optimization of initial mu agonist/delta antagonist lead compounds discovered in our laboratory. Our lead optimization strategy includes rational drug design utilizing crystal structure information on mu and delta receptors as well as multi-parametric approaches for the improvement of physicochemical and pharmacokinetic properties. To achieve the goal of identifying preclinical candidates, novel compounds are designed, synthesized, and evaluated for (1) opioid receptor binding and functional activity (2) pharmacokinetic profiling for metabolic stability, bioavailability, and CNS penetration, and (3) comprehensive profiling for analgesic efficacy and side effects in rodents. This team effort involves investigators from the University of Alabama at Birmingham, University of Arizona, and University of New England with extensive experience in computational modeling, opioid biochemistry, molecular biology, pharmacokinetics, opioid pharmacology and drug development.

For grant support and additional information see:

https://projectreporter.nih.gov/project_info_description.cfm?aid=8961201&icde=29274262

https://projectreporter.nih.gov/project_info_description.cfm?aid=7194350&icde=29274346

http://southernresearch.org/southern-research-awarded-5-year-4-5m-nih-grant-to-develop-opioid-drugs-with-diminished-side-effects/

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Subtype selective dopamine D3 receptor antagonists – Treatment agents for addiction and neuropsychiatric disorders

Dysregulation of the dopaminergic system is implicated in several pathological conditions including schizophrenia, Parkinson’s disease, depression, and addiction. Dopaminergic signaling is mediated through two types of receptors, the D1-like (D1, D5) and the D2-like (D2, D3, D4) receptors.

Among the various approaches, targeting the dopamine D3 receptor with antagonist or partial agonist ligands has emerged as a promising area for the development of medications for the treatment of schizophrenia, substance abuse, and neuropsychiatric disorders. The development of drug-like compounds with selectivity for the dopamine D3 receptor over the D2 receptor, however, has been challenging because of the high sequence homology between these two GPCRs. Based on modeling and experimental binding results with native and mutant receptors we have identified structural features that contribute to selectivity for a series of ligands possessing the acylaminobutylpiperazine framework. These insights are being utilized in the design and synthesis of novel compounds with enhanced potency and selectivity and improved physicochemical and pharmacokinetic properties to realize the goal of development of drugs for neuropsychiatric and substance abuse disorders.

For grant support and additional information see:

 

https://projectreporter.nih.gov/project_info_description.cfm?aid=8134448&icde=29274422

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Allosteric ligands of biogenic amine transporters – Molecular probes and potential antidepressants and analgesics

Discovery of ligands that modulate receptor function by binding to allosteric sites on biological targets has emerged as a promising new approach for finding drugs possessing significant therapeutic advantages over drugs that act as orthosteric ligands. Such allosteric modulators are currently being explored in-depth in the field of G-protein-coupled receptors.

Among the membrane bound targets in the central nervous system, the biogenic amine transporters in general, and the dopamine transporter (DAT) in particular, play a key role in addiction to stimulant drugs of abuse and in a number of psychiatric illnesses. Although ligands that are allosteric modulators of DAT have been of considerable interest, identification of such allosteric modulators has hitherto remained elusive. Starting with the discovery of a few lead compounds that displayed allosteric modulatory effects on DAT, through medicinal chemistry efforts we have evolved a second generation of ligands that display nanomolar dopamine uptake inhibition potencies with partial efficacy and with differential effect on substrate uptake versus release. Some of these ligands also display partial inhibition of serotonin uptake by serotonin transporter (SERT) and norepinephrine uptake by norepinephrine transporter (NET). Such triple reuptake inhibitors are potentially useful for treatment of depression and pain. Current efforts are focused on development of novel molecular probes for the biogenic amine transporters and drugs for the treatment of CNS disorders wherein such allosteric modulators may have a beneficial effect.

For grant support and additional information see:

https://projectreporter.nih.gov/project_info_description.cfm?aid=8698720&icde=29274472

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Sam Ananthan, Ph.D.

Principal Research Scientist, Chemistry Department

Sam Ananthan, Ph.D., is principal research scientist in the Department of Chemistry in Southern Research’s Drug Discovery division. In 1987, he joined SR as a research chemist, where he served as a group leader and manager of computational chemistry & CNS drug discovery chemistry before assuming his current position.

[ Read Full Bio Here ]

Lab Members

Phanindra Venukadasula, Ph.D.

Phanindra Venukadasula, Ph.D.

Associate Research Chemist

Phanindra Venukadasula, Ph.D., associate research chemist, obtained his M.S. from University of Hyderabad and his Ph.D. from University of Kansas working with Professor Paul Hanson. Venukadasula’s doctoral work involved the development of several phosphate-tether mediated one-pot metathesis processes and their application in synthesis of bio- active small molecules. He joined Southern Research in August 2012 as a postdoctoral fellow, where his accomplishments include synthesis of a variety of target compounds, developing structure-activity relationships, and sharing scientific findings via manuscripts and patent application. One of his major contributions is the identification of inhibitors of three proteases – matriptase, hepsin and HGFA – as a potential anticancer agents. These compounds were also selective against off-target enzymes, such as thrombin and factor Xa. Venukadasula’s is currently involved in the following projects: (a) HIV-Vif dimerization inhibitors, (b) Inducers of 14-3-3-Ɵ expression, and (c) RNA Pol1 Inhibitors.



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