The University of Mississippi
School of Pharmacy Department of Medicinal Chemistry

Ronald F. Borne Lecture

An annual event honoring Emeritus Professor Ron Borne

Ronald F. Borne image Image of Dr. Jacobson
Dr. Ronald F. Borne Dr. Kenneth A. Jacobson

2012-2013 Ronald F. Borne Lecture

 

Tuesday, April 30, 2013, 11 am: TCRC 2066


Dr. Kenneth A. Jacobson, Ph.D., Chief, Laboratory of Bioorganic Chemistry & Molecular Recognition Section, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health

"Topic: Structure-Based Discovery of Novel Ligands of GPCRs: Focus on Adenosine and P2Y Receptors"


Information available from:

662-915-7101

Mrs. Lowstuter

Borne Lecturer Info:

Dr. Jacobson got his Ph.D. at the University of California, San Diego, in 1981, after getting his B.A. at Reed College. Here is a summary of his research interests:

Dr. Jacobson is a medicinal chemist with interests in the structure and pharmacology of receptors and in developing drugs that act as agonists or antagonists of G protein-coupled receptors (GPCRs). The current focus is on receptors for purines, encompassing both adenosine receptors and P2 receptors, which are activated by ATP and UTP. Dr. Jacobson has taken an interdisciplinary approach to studying the chemical and biological aspects of these receptors. He has developed a "functionalized congener approach" to drug design. Novel ligands (small molecules) for these receptors are developed using classical synthetic approaches and also by semi-rational methods based on molecular modeling and template design. Receptors are computer-modeled by homology to rhodopsin, and the models for ligand recognition are tested and refined using site-directed mutagenesis of the receptor proteins. Recently, the involvement of extracellular loops of GPCRs have been implicated in the receptor binding of small molecules, as demonstrated through the mutagenesis and modeling of P2Y1 receptors.

Substances developed as potent and selective agents acting through adenosine and P2 receptors have proven useful as pharmacological probes and have potential for treating diseases of the central nervous system, immune system, and cardiovascular system. Recent accomplishments include the design and synthesis of the first A3 adenosine receptor agonists and antagonists, using a combination of library screening and optimization of known adenosine receptor ligands. These substances have been shown to be effective in models of treatment of glaucoma, cancer, stroke, and cardiac ischemia. A selective A3 adenosine receptor agonist developed in our laboratory is currently in clinical trials for colon carcinoma and rheumatoid arthritis. We have synthesized the first P2Y1 receptor-selective antagonists, through functionalization of adenine nucleotides. The antagonists were optimized with the aid of receptor homology modeling. These substances have been shown to be effective in models of antithrombotic treatment, due to blockade of the proaggregatory effects of ADP. The pharmacological probes designed in our section have been used to demonstrate the connection between purine receptors and apoptosis (programmed cell death). A3 adenosine receptor agonists at low concentrations and P2Y6 receptor agonists have antiapoptotic effects.

Another potential means of using the protective effects of AR activation was achieved through receptor engineering. Constitutively active mutant A3 adenosine receptors, in principle, could be delivered by tissue-targeted vectors for gene therapy. In addition, we have introduced the approach of “neoceptors”, also intended for eventual use in gene therapy, in which the putative agonist binding site is redesigned to accept only agonist molecules altered in a complementary fashion. Insight into the recognition of agonist by the receptors may be gained using site-directed mutagenesis and molecular modeling. We are exploring this approach conceptually with tailor-made agonist ligands (“neoligands” that are selective for the neoceptor and not the native receptor) in combination with receptor mutagenesis. The neoceptor concept has so far been applied to A2A and A3 adenosine receptors.

Last Year:

2011-2012 Ronald F. Borne Lecture

An annual event honoring Emeritus Professor Ron Borne

Ronald F. Borne image Dr. S. Michael Owens
Dr. Ronald F. Borne Dr. S. Michael Owens

2011-2012 Ronald F. Borne Lecture

 

Tuesday, April 10, 11 am: TCRC 1000


Dr. S. Michael Owens, Professor and Director, Center for Alcohol and Drug Abuse, and a Wilbur Mills Endowed Chair in Alcohol and Drug Abuse Prevention, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences

"Therapeutic antibodies for the treatment of addiction – At the interface of chemistry and biology"


Information available from:

662-915-7101

Mrs. Lowstuter

Borne Lecturer Info:

Dr. Owens got his Ph.D. at the University of North Carolina, Chapel Hill, in 1980. Here is a summary of his research interests:
The objective of my research program is to develop antibody-based medications for use in treating the neurological problems associated with drug abuse. The projects involve the integration of multidisciplinary basic science studies with the application of these scientific discoveries to the treatment of human disease. These studies utilize molecular design, hybridoma technology, antibody engineering techniques, as well as studies of the effects of drug of abuse on brain function. Large scale production of antibodies as drugs is accomplished through the use of bioreactors, along with the development of the technology for the molecular and biological engineering of plant-derived antibodies. For the in vivo testing of the antibody-based medications, a comprehensive series of pharmacokinetic/pharmacodynamic studies following active and passive immunization are being conducted in animal models of human drug abuse. A major goal of these studies is to better understand the mechanism by which these new medications can be used to treat adverse chemical effects on the central nervous system. Thus, these studies are serving as a prototypic system to acquire knowledge that can be applied to antibody-based therapy for a wide variety of human diseases.

 

Previous Year:

2010-2011 Ronald F. Borne Lecture

An annual event honoring Emeritus Professor Ron Borne

Ronald F. Borne image Bruce E. Maryanoff image
Dr. Ronald F. Borne Dr. Bruce E. Maryanoff

2010-2011 Ronald F. Borne Lecture

Thursday, April 21, 11 am: TCRC 1000

Dr. Bruce E. Maryanoff, PhD Department of Chemistry, The Scripps Research Institute

“Adventures in Drug Discovery: Enzyme Inhibitors, Receptor Antagonists ... and More“

Information available from:

662-915-7101

Mrs. Lowstuter's Webpage

2010-2011 Borne Lecturer Info:

Bruce Maryanoff has been active as a medicinal and organic chemist. He invented TOPAMAX topiramate, a unique sugar sulfamate drug, marketed worldwide for treating epilepsy and migraine, with annual sales >$2 billion. He is an internationally renown expert in drug design and discovery, esp. the application of protein structure-based drug design. Since 1991 he pursued cardiovascular therapeutics, while seeking drugs for pulmonary inflammation, metabolic disorders, and epilepsy. In the past 15 years, his drug research has dealt with structure-based drug design; peptides/peptidomimetics; enzymes inhibitors, esp. serine proteases/kinases; integrin antagonists; ligands for G-protein-coupled receptors. His efforts led to many new chemical entities entering preclinical development, with 13 advancing into human clinical trials. He made seminal contributions to understanding stereochemistry and mechanism of the Wittig reaction; devised novel peptides that self-assemble to mimic native collagen. Maryanoff is an author on 270 scientific publications, including books (Editor), book chapters, review articles. He is an inventor on 100 U.S. patents (issued/pending), presented >150 invited lectures, mentored 11 postdocs. He is Assoc. Editor of ACS Med. Chem. Lett.; organized/edited a special issue of J. Med. Chem. to honor Dr. Paul Janssen; has served on editorial advisory boards for journals and research grant committees. Maryanoff received two American Chemical Society national awards, and the prestigious Smissman Award from the Med. Chem. Division of the ACS; was inducted into the ACS Medicinal Chemistry Hall of Fame in 2008; was elected Fellow of the ACS, Amer. Assoc. for the Advancement of Science, and Royal Society of Chemistry. He retired from Johnson & Johnson in Jan 2010, after 36 years of service, and is now affiliated with The Scripps Research Institute (La Jolla, CA); Pennsylvania Drug Discovery Institute (Doylestown, PA); Institute for Hepatitis and Virus Research.