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).

Major Research Programs

  • 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.

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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.

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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.

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  • Publications

Meet Our Researchers

Sam Ananthan, Ph.D. | Fellow, Chemistry Department

Sam Ananthan, Ph.D., is a fellow in the Chemistry Department 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. Ananthan is one of the founding members of the Center for Neuromolecular Research. His main research interests include lead discovery and lead optimization using rational drug design and medicinal chemistry approaches for development of novel preclinical candidates. Ananthan is a principal investigator on several grants and contracts from the National Institute on Drug Abuse (NIDA) and the National Institute of Allergy and Infectious Diseases (NIAID). He received his doctorate in synthetic organic/medicinal chemistry from Gujarat University, Ahmedabad, India, in 1984, after which he completed a three-year, post-doctoral study investigating bioreductively activated anticancer agents with Professor Donald T. Witiak in the Department of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio. Ananthan is also an adjunct professor of chemistry in the Department of Chemistry at the University of Alabama at Birmingham.

Phanindra Venukadasula, Ph.D. | Associate Research Chemist

Venukadasula earned his doctorate from the University of Kansas and his master’s from the University of Hyderabad, where his work involved the development of several phosphate-tether mediated one-pot metathesis processes and their application in synthesis of bio-active small molecules. SR accomplishments include: synthesis of a variety of target compounds; structure-activity relationships; and scientific findings shared via peer-reviewed publications and patent applications. One of his major contributions is the identification of inhibitors of three proteases – matriptase, hepsin and HGFA, as potential anticancer agents. This work resulted in the only known small molecule inhibitor of HGFA. These inhibitors were also selective against off-target enzymes, such as thrombin and factor Xa. He worked on small molecule inducers of 14-3-3Ө expression as a potential therapy for Parkinson’s disease. He designed and synthesized a series of compounds of which one analog has been identified as a potent lead compound. His current research involves the design, synthesis and development of small molecule inhibitors of HIV-Vif dimerization and inhibitors of Vif-mediated degradation of A3G as novel targets for development of HIV-targeted drugs. Publications