Antibodies are powerful tools to explore signal transduction pathways. In a recent effort, NIDA-funded researchers have developed an integrated approach that combines a strategy of antibody development, a time- and cost-effective method of antibody validation, and a high-throughput microscopy/machine learning pipeline to identify antibodies. Using yeast display antibody libraries from the B cells of immunized rabbits and high-throughput functional screening they identified and validated 137 recombinant high affinity antibodies against understudied synaptic proteins. These antibodies could serve as potential tools to shed light on signaling in the central nervous system.
Using a subset of antibodies targeting the opioid receptors they examined the effect of morphine and fentanyl on mu opioid receptor phosphorylation and signaling. Their studies revealed differences in the rate, extent, and site of opioid receptor phosphorylation induced by morphine and fentanyl, thus highlighting the complexity of opioid signaling and illuminating ligand-dependant differential activation and desensitization of mu opioid receptors. These molecular differences may be relevant to the acceleration in opioid overdose deaths that have been attributed to increased use of fentanyl.
- Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor
Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used for recreational purposes. In addition to their recreational use, substances such as psilocybin are being considered as therapeutics for many neuropsychiatric disorders including depression, anxiety, and substance abuse. Although the precise mechanisms of action of hallucinogens remain unclear, agonist activity at the 5-HT2A serotonin (5-hydroxytryptamine [5-HT]) receptor is known to play an essential role in their psychedelic effects in humans.
In a landmark study, NIDA-funded scientists have solved active state structure of a prototypical hallucinogen 25-CN-NBOH bound to 5-HT2A receptor in complex with an engineered αq heterotrimer by cryoelectron microscopy (cryo-EM). They also obtained X-ray crystal structures of the arrestin-biased agonist LSD and the inverse agonist methiothepin bound to 5-HT2A receptor. These structures provide insights into the molecular details of both ligand recognition and coupling to the intracellular effectors that are key to gaining a molecular understanding of hallucinogen actions. Moreover, these studies provide a framework for a structure-guided search to identify more selective and efficacious HT2A receptor agonists as potential therapeutic agents for neuropsychiatric disorders.
What We Do:
The Chemistry and Pharmacology Branch (CP) supports research on all aspects of chemistry and pharmacology affected by drugs of abuse. The CP Branch maintains, develops, and oversees a portfolio encompassing research, such as:
- Elucidating mechanisms of action, structure-activity relationships, understanding of basic principles involved with biological activity, pharmacology and toxicity,
- Developing new receptor type and subtype specific agents and,
- Supporting research on the pre-clinical development of new pharmacotherapies for the treatment of drug abuse disorders emphasizing the pre-clinical stages of target identification through hit-to-lead.
This branch supports research programs on
- Elucidate effects of drugs on all the physiological systems including the central nervous system and the other physiological systems such as the cardiovascular, pulmonary, and immune.
- Using synthetic, medicinal, Structure-activity studies (SAR) and pharmacological approaches, develops probes for basic research and potential drug leads to treat addictive disorders; Elucidates the chemical mechanism for drug addiction,
- The discovery of endogenous ligands, and the role of endogenous ligands and systems relevant to drug action, and addiction
- The studies of absorption, metabolism, pharmacokinetics, pharmacodynamics, elimination, transport and delivery
- Investigations on analytical methods development, proteomics, protein folding and related functional genomics and structural biology
- Synthesis, structure-function relationships, conformational studies, structural biology, ligand design of all drugs abuse; synthesis of affinity reagents, chemical probes, drug-receptor interaction model to elucidate drug action
- Pharmacological approaches to understand perinatal drug exposure and the effects of confounding factors, such as, maternal and environmental stress, nutrition etc., on neural systems and other organs utero.
Research Interests and Biographies
Subramaniam Ananthan, Ph.D. - Chief
Dr. Subramaniam (Sam) Ananthan, is the Chief of the Chemistry, Pharmacology, Physiology Branch. Dr. Ananthan is a medicinal chemist with more than 30 years of experience in the discovery and development of new therapeutics for the treatment of pain, addiction, and other central nervous system disorders. Following his postdoctoral research with Professor Donald T. Witiak at The Ohio State University, he joined Southern Research Institute in 1987 where he held various positions from a research chemist to a Fellow. He also served as an Adjunct Professor of chemistry at the University of Alabama at Birmingham (UAB). He has been a Principal Investigator on multiple grants and contracts and a recipient of continuous funding from NIDA for more than 25 years. His NIDA-funded research has focused on the development of opioids possessing mixed functional activity, D3 receptor antagonists for treatment of substance use disorders, and allosteric regulators of the dopamine transporter for treatment of substance use disorders. He has published over 85 peer-reviewed papers in the areas of medicinal chemistry and structure-based drug design. He is an inventor on 21 U.S. patents and has been inducted as a Fellow of National Academy of Inventors (NAI). He has been an active member of the American Chemical Society and has served as a Long Range Planning Committee member in the Division of Medicinal Chemistry. and expertise, we look forward to seeing how his leadership will shape the field.
Kiran Vemuri, Ph.D. - Program Officer
Dr. Kiran Vemuri’s career in science spans over two decades across both industry and academia of which, he spent 15 years developing research tools and studying novel treatments for substance-use disorders. His research interests broadly include chemical synthesis, route selection and optimization, in vitro and in vivo pharmacology, and the therapeutic assessment of biologically active compounds. After receiving his Ph.D in chemistry from Osmania University, India, Dr. Vemuri worked at Northeastern University, Boston, as faculty, ultimately taking on the role as Deputy Director at the University’s Center for Drug Discovery. Notably, Dr. Vemuri’s research on pseudo-irreversible tight binding ligands led to determining the crystal structures of both the human CB1 and CB2 cannabinoid receptors. Dr. Vemuri is known for his research on CB1 neutral antagonists that are devoid of CNS liabilities and their positive effects on metabolic profiles. Beyond addiction science research, he actively worked on the early- and late-stage discovery, and the development of therapeutics for treating diabetic nephropathy, pulmonary inflammation and fibrosis, and liver complications involving steatohepatitis and fibrosis. Dr Vemuri holds 20 issued patents, and has contributed to more than 65 peer-reviewed papers.
Paul S. Hillery, Ph.D. - Health Scientist Administrator
Supports research in organic & medicinal chemistry, structural biology.
Paul. S. Hillery, Ph.D. Health Science Administrator, has a background in organic and medicinal chemistry, based on NIH intramural research and review of drug design/manufacturing in INDs and NDAs for the FDA. Since 1996, Paul Hillery has served as an administrator of assigned NIDA grants in the areas of cannabinoid, nicotinic, and opioid research, pertaining to receptors and transporters having relevance to drug abuse. The grant portfolio has been quite varied, but focused mostly on probes, leads, and methods from a basic research perspective.