What Challenges?

How do we prepare students for a career in Pharmacology?

How do we combine elements of “traditional pharmacology with modern concepts and discoveries?

Are students getting a solid foundation of the basics?

How do we stay current as instructors and teachers?

How do we determine if we are doing a good job?

Pharmacology at UNCBasic Structure/ Core CoursesFall-1st YearPHCO 201- Introduction to Molecular PharmacologyPHCO 331- Pharmacology Seminar Spring-1st YearPHCO 202- Principles of Pharmacology

Fall-2nd YearPHCO 220- BiostatisticsPHCO 330-Current Topics in Pharmacology

Spring-2nd YearPHCO 330- Current Topics in PharmacologyPHCO -Electives/ Special Topics

Pharmacology at UNC

Some General Things We Do:

ComputersAll 1st year graduate students receive new lap top computerswith “wire-less” internet capabilities. Students can access WEB information during class, useful for teaching Bioinformatics, structural anaylsis and biostatistics.

CoursesCourses organized into “blocks” with Block-heads organizing the block content, instructors, exams etc.Integrate required aspects of Physiology, Biochemistry and Genetics as needed to prepare students for Pharmacology.

PHCO 201 “Introduction to Molecular Pharmacology” Fall Semester2004Monday and Wednesdays 9:00 - 9:50 AM 1102 Mary Ellen JonesBuildingCourse Directors: JoAnn Trejo and David Siderovski

Topic Lecture hours Block LeaderI. Genes to Protein/Molecular Biology 8 SiderovskiII. Receptors/Ion Channels 5 Rosenberg

Regulation of Second Messengers 4 DohlmanIII. Principles of Drug/Receptor Interactions 6 Harden

Metabolism 4 Graves

I. Genes to Protein/Molecular BiologyW August 25 Course Introduction (Trejo/Siderovski);

Central Dogma of Genetic Information (R. Kole)M August 30 RNA as a Therapeutic Target (R. Kole)W September 1 Introduction to Bioinformatics Part I (Siderovski)M September 6 (HOLIDAY) NO CLASSW September 8 Techniques of Protein Purification/Structure Determination (Betts)M September 13 Introduction to Bioinformatics Part II (Siderovski)

(Assignment of Take-home Exam I - due Friday Sept. 24th, 5PM)W September 15 Structural Bioinformatics (Temple)M September 20 Techniques of Gene Manipulation/Macromolecular Therapeutics

(Miyamoto)W September 22 Gene Therapy (Samulski)M September 27 Take up session of EXAM I

II. Receptors/ Ion Channels and Regulation of Second MessengersW September 29 Historical Perspective (K. Harden)M October 4 GPCRs (J. Trejo)W October 6 Nuclear Receptors (K. Korach)M October 11 Ion Channels (R. Rosenberg)W October 13 RTK’s (S. Earp)M October 18 Activation and inactivation of G proteins (includes RGSproteins)

Introduction to effectors and second messengers (H. Dohlman)W October 20 Activation and inactivation of ras-family GTP binding proteins(C. Der)M October 25 Activation of PKA by cAMP, regulation of cAMP by cyclaseand

PDEs.(L. Graves)W October 27 Activation of CaM kinase and PKC and PKC by PLC, DAG, IP3,

and calcium second messengers (McCarthy/Harden)M November 1 EXAM II

III. Principles of Drug/Receptor Interactions and Drug MetabolismW November 3 Drug receptor interactions (K.Harden)M November 8 “W November 10 “M November 15 “W November 17 “

The “Core” CoursesPHCO 201/202

PHCO 201- 2 credit hours

Course Objectives:To introduce basic and essential concepts of Pharmacology to preparestudents for detailed mechanism of drug action covered in PHCO 202.

Introduction to Bioinformatics I

“Machine-readable biological information”

Dr. David P. Siderovski

Department of Pharmacology

Sept. 1st, 2004

The Entrez System

Use your computer’sclipboard: ^C & ^V

(or command-C & command-V)

p

CYTOGENETIC MAP POSITION:

q

Associating Disease with Genomic DNA:Karyotype analyses

Tell me everything that’s ever been found here…

www.ensembl.org

The Future of Chemotherapy Patient Profiling?The Future of Chemotherapy Patient Profiling?

Proteins

Chemical library

HTS results

SAR analyses

Combi-chem synthesis

Assign pharmacophore

ADME / Tox workup

In vitroADME / Tox

Don’t delay triage ofcompounds that aren’t

“drug-like”

HTS for Absorption - Model membrane assay:

Detect via UV spectroscopy(faster than LC/Mass Spec)

HTS for Absorption - SPR with liposome surface:

Danelian, E. (2000) J. Med. Chem. 43:2083-6.

Structure Databases

Estrogen ReceptorPDB Molecule of the Month

Protein Data Bank (PDB) with > 22,700 structures

Cambridge Structural Database (CSD) with > 250,000 structures

Text or Sequence Similarity

http://www.rcsb.org

Structural Neighbors Databases• Structural Neighbors Databases

CATH, SCOP, CE, VAST, FSSP

Horse liver alcohol dehydrogenase

Silverleaf whitefly ketose reductase

Gprotein beta subunit

Pharmacology 202 (Spring 2005)Principles of Pharmacology

Mon, Wed Fri, 9:00-9:50, 1102 MEJCourse Director: Leslie Parise (1021 MEJ; 966-2238; parise@med.unc.edu

mic/autocoid/endocrine-- Ken McCarthyWed. Ken Harden Anatomy & Physiology of Autonomic Nervous SystemFri. Ken Harden Synthesis, Storage, Release and Metabolism of CatecholaminesMon HolidayWed. Ken Harden Alpha Adrenergic ReceptorsFri. Ken Harden Beta Adrenergic ReceptorsMon. Ken Harden Ken Harden sick Wed. Ken Harden Sympathomimetic AgentsFri. Shelly Earp Pathogenesis/Pathophysiology and Treatment of DiabetesMon. Ken Harden Adrenergic AntagonistsWed. Ken Harden Review sessionFri. David Ontjes Calcium Homeostasis and Associated DisordersMon. Ken McCarthy Parasympathetic Nervous SystemWed. Ken McCarthy Drugs affecting the Parasympathetic Nervous SystemFri. Gary Johnson Treatment of GI DisordersMon. Rudy Juliano Autocoids, Histamine and AntihistaminesWed. Rudy Juliano Eicosanoids, Anti-inflammatory Drugs, Non-narcotic analgesicsFri. Exam

nal--Bob Rosenberg/Leslie PariseMon. Bob Rosenberg CV Physiol reviewWed. Lee Graves AntihypertensivesFri. JoAnn Trejo DiureticsMon. JoAnn Trejo DiureticsWed. Leslie Parise Atherosclerosis and AntihyperlipidemicsFri. Leslie Parise Anticoagulants and anti-platelet agentsMon. Bob Rosenberg Antiarrhythmics

Wed. Cam Patterson AnginaFri. Cam Patterson Heart Failure (receive take-home exam on CV/Renal)

Richard Mailman and Clyde Hodge

Mon.RichardMailman

Overview of Pharmacology of CNS (psychiatric and neurologicdisorders)

Wed.RichardMailman

Antipsychotic Drugs (dopamine and serotonin mechanisms):

Fri. Holiday

Mon.RichardMailman

Drugs for ParkinsonÕs and AlzheimerÕs Disease (dopamine, Ach, etc.):

Wed.RichardMailman

Psychostimulants & Hallucinogens (dopamine & serotonin):

Fri.RichardMailman

Drugs for Mood Disorders (norepinephrine & serotonin):

Mon. Clyde Hodge Ionotropic Drugs & the CNS: Anxiolytics (GABA)

Wed.Clyde Hodge Ionotropic Drugs & the CNS: Antiepileptics & Alcohol (GABA &

Glutamate)

Fri.RichardMailman

CNS Analgesics & Drugs of Abuse (Opioids)

Mon. CNS Exam CNS Exam

PHCO 202- 3 credit hours

Course objectives:To teach classicalmechanisms of drug actioncombined with currentresearch discoveries and directions.

Course parallels the MEDPHARM course taught to Med students. The differenceis the amount of mechanismand current research.

PHCO 202 Principles of Pharmacology

Example: My lecture on anti-hypertensive agents

1st-half- classical approaches to treat hypertensionMechanism of action of different drug classesStandard view of hypertension treatment

2nd- half- current research in anti-hypertensiveDogma challenging research and re-evaluation of Status-quo.Mechanism of action of novel therapeutics

Antihypertensive Drugs

• Drugs Classes• 1. Angiotensive converting enzyme inhibitors- Enalapril,

Captopril• 2. Angiotensive receptor antagonists• 3. Aldosterone antagonists• 4. Diuretics• 5. Ganglionic blockers• 6. receptor antagonists• 7. receptor antagonists• 8. Direct vasodilators• 9. 2 receptor agonists in CNS• 10. Noradrenergic neuron blockers

Renin/Ang System

PHCO 202 Principles of Pharmacology

Incorporation of Current Research Topics

Med line searches- updated analysis on drug successesor failures.

Assign a manuscript to read: often a current review or research paper to prepare students for specific topics.

The shift in the "paradigm" of the pharmacology of hypertension.Flordellis CS, Goumenos D, Kourounis G, Tsementzis SA, Paris H, Vlachojiannis J.Curr Top Med Chem. 2004;4(4):487-98.

Dual ACE and neutral endopeptidase inhibitors: novel therapy for patients with cardiovascular disorders.Tabrizchi R. .Drugs. 2003;63(20):2185-202.

ExamsStill test the basics!Multiple choiceand problem solvingQuestions

Course evaluationscollected- feedbacksought.

Implementing “smallGroup” strategies toteach key concepts

Electives- “Filling in the Gaps”

Some examples:

1. Gene Therapy: Medicine for the 21st Century-Samulski

2. Discovery Biology and Pharmacogenomics- Siderovski, Sondek

3. Protein Kinases as Targets for Novel Pharmacological Inhibitors-Graves, Johnson.

4. Ras Superfamily and Signal Transduction- Der , Cox

5. Molecular Pharmacology of Cancer-Kole