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PHARMACOLOGY

 

March 21-22, 2009


General Program

Friday Evening, 3/20

Opening Reception (7:00 PM)

Saturday, 3/21

Plenary symposium on 5-HT2C receptors as novel targets

Special Lecture - Dr. Richard Glennon

Student Oral Presentations

Poster Session

Dinner, Awards, and After Dinner Speaker - Dr. Terry Kenakin

Sunday Morning, 3/22

Open Oral Communications

Special Lecture - Dr. Thomas Kosten

Closing remarks and adjournment (2:00 PM)

 

 
 

INVITED LECTURES

Dr. Richard A. Glennon is an internationally recognized expert in medicinal chemistry and behavioral pharmacology. Richard Glennon was awarded his doctor of philosophy degree in medicinal chemistry from the State University of New York at Buffalo. He is currently professor and chair of the Department of Medicinal Chemistry at Virginia Commonwealth University. Dr. Glennon’s major research interests are in the areas of neuropsychiatric disorders, CNS medicinal chemistry, and drug abuse (with an emphasis on hallucinogens). He has published more than 400 scientific papers, and trained more than 100 graduate students, post-docs, and visiting scientists.  Because of his dual expertise in medicinal chemistry and behavioral pharmacology (especially drug discrimination), and because of his extensive training record, Dr. Glennon’s participation will contribute greatly to our meeting achieving its scientific and educational goals. The lecture by Dr. Glennon will provide an overview of how chemistry and biology interact and work cooperatively using structure-activity relationships to develop drugs. 


Behavioral Studies and SAR

Richard A. Glennon, Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298


Normally, formulation of structure-activity relationships (SARs) is not a terminal research goal but is, rather, a means to an end. That is, armed with information about SAR, the tasks of drug design and development (e.g. identification or optimization of new chemical entities or NCEs) can be facilitated. For example, knowledge of SAR can be applied to optimize the actions of a known agent (lead optimization), or can be employed to create a pharmacophore model that might be exploited for developing newer agents with entirely novel structures. SAR data can be used in a comparative fashion to determine if two series of agents are behaving similarly (i.e., parallel structural changes in two series of agents generally result in parallel shifts in activity if the two series are behaving in the same manner). They can also be employed for classification studies to determine what members of a series of agents produce which of two actions, and how structural features account for these actions. Quantitative structure-activity relationship (QSAR) studies aim to identify why chemical structure influences activity/potency by relating the physicochemical properties of substituent groups to effect. Correlational studies can identify relationships between agents and some other parameter (e.g. radioligand binding, functional activity) and how structure relates to these actions. Using, primarily, a two-lever operant drug discrimination technique with rats as subjects, we have formulated SARs for several classes of compounds and applied this information to subsequent drug studies. Certainly, there are caveats when using in vivo assays, various potential problems need to be considered including absorption, metabolism, and the ability of agents to penetrate the blood-brain barrier. But even here, SAR studies can provide clues on how to overcome these problems, and the technique has proved successful. Examples from several studies conducted in our laboratories will be used to illustrate the concepts involved. 

 

 
 

Dr. Terry Kenakin is an internationally recognized expert on receptor theory and drug development.  Terry Kenakin received a Ph.D. in Pharmacology at the University of Alberta, Edmonton Canada.  After a post-doctoral Fellows in London, U.K. with the nobel laureate Sir James Black, he joined Burrough-Wellcome as an associate Scientist.  From there he continued working in drug discovery at Glaxo Inc. and GlaxoWellcome.  Presently he is a principal research scientist at GlaxoSmithKline Research and Development Laboratories at Research Triangle Park, N.C. USA.  Dr. Kenakin has been involved in drug discovery for over 27 years.  Currently, he is engaged in studies aimed at the optimal design of drug activity assay systems as well as the discovery and testing of molecules to block the entry of HIV-1 for treatment of AIDS.  He is a world authority on the subject of receptor theory and is a member of numerous editorial boards as well as Co-Editor in Chief of the Journal of Receptors and Signal Transduction and, as well as numerous articles, has written seven books on Pharmacology.


The Chemist-Biologist Interface in Drug Discovery: Forming a Basis of Understanding

Terry Kenakin, GlaxoSmithKline Research and Development Laboratories at Research Triangle Park, N.C. USA. 


At the heart of a successful drug discovery program is a good working relationship between chemists and biologists. This is not necessarily automatic as each comes from a rather different scientific background. Moreover, pharmacology is largely a science of biological behavior which can vary when targets mediate response in different organs and tissues. Therefore, it is important that chemical information about drug activity in biological systems be made available to medicinal chemists in drug discovery programs. If this can be done, dissimulations due to variances in biological systems (i.e. changing basal setpoints, genetic and biochemical variability etc.) can be avoided. The application of four major pharmacodynamic parameters (affinity, efficacy, orthosteric vs allosteric binding, rate of drug dissociation) to quantify primary biological activity to chemical structure-activity relationships (SAR) will be discussed.  These four parameters can be used to quantify effect in test systems and predict subsequent activity in the therapeutic setting. In total, these data can provide system independent data to characterize biological activity of molecules in chemical terms that can be used to predict drug activity in all biological systems.

 

 
 

Dr. Thomas R. Kosten is an internationally recognized expert in addiction research.  He received his M.D. at Cornell University Medical College/New York, NY. Thomas Kosten is a Professor of Psychiatry and Neuroscience at Baylor College of Medicine and former Professor and Chief of Psychiatry at Yale University and VA Connecticut. He is founder of the Division of Substance Abuse at Baylor and Yale and directs their NIH Medications Development Center for substance abuse. Dr. Kosten’s research involves translational neuroscience and behavioral pharmacology.  From his studies in substance dependence, post traumatic stress disorder, and neuroimaging he has published over 450 papers, books and reviews. His neuroimaging research includes detecting and treating cocaine induced cerebral perfusion defects, and using functional MRI to predict pharmacotherapy outcome. His medication contributions include a cocaine vaccine, immunotherapy for hallucinogens, buprenorphine for opioid dependence, disulfiram for cocaine dependence, vasodilators for cocaine induced cerebral perfusion defects, and combining medications with contingency management for opioid and cocaine dependence.


Pharmacotherapy of stimulants:  From Antabuse to Vaccines

Thomas Kosten MD, Frank Orson MD, Alison Oliveto PhD and Therese Kosten PhD,   Baylor College of Medicine and Michael E DeBakey VA Medical center


The pharmacotherapy of stimulants has yet to have an FDA approved medication, but two promising medications have opened up new concepts in treatment – pharmacogenetics and immunotherapy.  Pharmacogenetics means that a medication is matched to a patient’s specific genetic DNA coding.  This matching depends on a genetic polymorphism influencing the expression of an enzyme, receptor, transporter or other protein important for the action of that medication and the disease.  We have found that levels of the enzyme dopamine beta hydroxylase (DBH) are regulated by a polymorphism affecting about 40% of the population and leading to 10 to 100 times less enzyme than “normal”.  This enzyme converts dopamine to norepinephrine, and it can be inhibited by disulfiram (DS).  Seven clinical trials have found that DS reduces cocaine abuse, and we recently found that patients with the DBH polymorphism leading to low DBH enzyme levels specifically respond to DS treatment, while those without this polymorphism do not reduce their cocaine abuse.  This pharmacogenetic association has been replicated, and we have started new clinical trials with a new better medication for inhibiting DBH – nepicastat.


Immunotherapy involves producing anti-drug antibodies that reduce drug levels in the brain by binding drug before it enters the brain.  Because antibodies are much larger than drugs, neither the antibody nor bound drug can get into the brain.  Thus, any drug that is bound to antibody cannot cross the blood brain barrier and cannot enter the brain.  Active anti-drug vaccines stimulate the body to makes its own antibodies by chemically linking these abused drugs to toxins such as cholera toxin. Alternatively, passive immunotherapy uses monoclonal antibodies that are generated in a laboratory and then administered via intravenous injection.  This talk will review the advances made with immunotherapies for cocaine, but similar vaccines are being developed for nicotine, methamphetamine, heroin and other drugs of abuse.  Both the nicotine and cocaine vaccines have been tested in humans with excellent success for attaining abstinence and preventing relapse, but antibodies also can treat drug overdose or protect certain at risk populations who have not yet become drug dependent. 

 

 
 

SYMPOSIUM


Title: 5-HT2C receptors as novel targets for the treatment of addiction


Over the past several years considerable evidence has accumulated which establishes a prominent role for the 5-HT2C receptor in various aspects of addiction. Notably, the 5-HT2C receptor regulates the activity of mesolimbic dopaminergic neurotransmission which is activated by addictive drugs. 5-HT2C receptors display a highly dynamic repertoire of characteristics which may be exploited to develop novel medications for treatment of various drug addiction-related behaviors.



Dr. Kathryn Cunningham is the Chauncey Leake Distinguished Professor of Pharmacology, Director of the Center for Addiction Research, and Acting Chairman of the Department of Pharmacology and Toxicology at the University of Texas Medical Branch (UTMB) in Galveston, Texas. Dr. Cunningham studies the role of serotonin neurotransmission in behavior, and is considered one of the world leaders in the role of serotonin in drug abuse and addiction. She will speak about pharmacological and anatomical studies pinpointing the critical roles of the 5-HT2A and 5-HT2C receptors in the behavioral response to abused drugs.

 

 
 

Dr. Kelly Ann Berg is an Assistant Professor in the Department of Pharmacology at UTHSCSA and is an expert on receptor theory. She has been studying receptor signaling mechanisms for the past 25 years and will speak about mechanisms of novel actions of drugs acting via 5-HT2A and 5-HT2C receptors that produce different signaling profiles and regulate constitutive receptor activity.

 

 
 

Dr. Scott Gilbertson is a Professor and the Robert A. Welch Distinguished University Chair in Chemistry and the Director of the Program in Chemical Biology at UTMB. His research is centered on the development of new synthetic methods and the utilization of synthetic chemistry for the study of important biological and medical problems. He will speak about the use of synthetic chemistry strategies to produce novel 5-HT2 receptor ligands.

 

 
 

Dr. Amarnath Natarajan is an Assistant Professor in the Department of Pharmacology and Toxicology at UTMB. His research focuses on the use of small molecules, developed from synthetic chemistry methods, to perturb phospho-specific protein-protein interactions as a first step towards understanding how cells exploit these interactions in signal transduction. He will speak about the targeting of these protein-protein interactions for drug development.

 

 
 

OTHER PRESENTATIONS


Student Oral Communications

The Program Committee will select 12 submitted abstracts from students who indicate a wish to give a 15 min oral presentation. The order of presentations will be organized according to themes (e.g., drug class) although papers on any topic, from clinical to basic science, will be eligible for presentation. Students who are not selected for this oral communications session will be included in the poster session. To the extent possible, the Program Committee will select four undergraduate, four graduate, and four post-graduate students for oral presentations. The top 3 presentations, as judged by the Awards Committee, will each receive a monetary prize.


Poster Session

The poster session will include refreshments and light snacks.  The Awards Committee will listen to oral poster presentations from undergraduate, graduate, and post-graduate students who indicate that they wish to participate in the poster competition. The top 3 presentations, as judged by the Awards Committee, will each receive a monetary prize.


Open Oral Communications

The Program Committee will select 12 submitted abstracts for 15-minute oral presentations.  The order of presentations will be organized according to themes (e.g., drug class) although papers on any topic, from clinical to basic science, will be eligible for presentation.  Presenters in this session might also include students.