Drug discovery techniques - a specialist course for undergraduate pharmacologists

1. Drug discovery techniques - a specialist course for undergraduate pharmacologists James A. Angus & Christine E. Wright Department of Pharmacology University of Melbourne Victoria 3010 Australia

2. 2000 in vivo practical teaching – Australia & NZ

3. Systems covered by practicals

4. Techniques used by students

5. Current in vivo practicals – 1 • CNS/Autonomic • Rat: sedation, hypnotic effects & anaesthesia • Conscious rabbit: baroreflex & other reflexes • Mouse: routes of drug administration, sleeping times, behavioural effects • Student: ocular effects of drugs; ethanol & psychomotor function • Analgesia • Mouse: tolerance & dependence to morphine • Student: local anaesthetics • Renal • Student: diuretic drugs

6. Current in vivo practicals – 2 • Cardiovascular • Conscious rabbit: cardiovascular control; central vs. peripheral antihypertensive drugs; renin-angiotensin • Student:b-blockers & exercise; glyceryl trinitrate • Metabolism • Mouse: pentobarbitone in liver • Student: aspirin excretion; ethanol, pharmacokinetics • Asthma • Student: Ventolin, glyceryl trinitrate & histamine • Inflammation • Guinea pig: cutaneous & systemic anaphylaxis

7. 2002 in vivo practicalsBSc third year ≈ 2 x 30 students • Drugs affecting reflex control of blood pressure • to compare the responses to pressor & depressor agents ± sympathetic & parasympathetic cardiac nerve blockade in conscious rabbits • Angiotensin-converting enzyme inhibition • to compare the responses to angiotensin I, angiotensin II & bradykinin ± ACE inhibition in conscious rabbits

8. Problems – 1 • Animal ethics • Pressure to decrease animal numbers • Difficult to convince that use of animals has benefits over computer simulation • Staff training • Loss of expertise • More trained demonstrators per practical • Expense & equipment • Animal cost (especially larger species) • Lack of sophisticated equipment

9. Problems – 2 • Class sizes & time slots • eg. Melbourne University Science 3rd year students increased from 30 to 70 in last 3 years • 6 hour practicals becoming a luxury • Pressure to develop computer simulations or demonstrations for all subject areas • Student reluctance

10. The fall & rise of in vivo pharmacology- In Vivo Pharmacology Training Group TiPS 23: 13-18, 2002

11. “in vivo training & knowledge MUST be given proper emphasis in any pharmacology courses that are offered now & for the foreseeable future” UK 1977: BSc - all incorporated in vivo pharmacology 1997: 27 university depts. running BSc pharmacology; 9 had somein vivo training • Why: economics - too expensive staff training/skills - retired molecular biologists • Home office - society pressure • Student numbers - fees • Modular courses • Careers - pharmacology not outcome

12. Science III - Pharmacology PracticalLent Term 1968 -Obtained from University of Sydney

13. “Brave new post-genomic world” • Targets: • 30,000 genes to protein products • Testing: • robotics, high throughput screening • Compounds: • combinatorial chemistry & natural products • Bioinformatics: • virtual chemical libraries, computer modelling

14. What molecular biology, in vitro studies & computer technology cannot do • Integrated response • molecule to man • Reveal the unexpected • secondary actions, selectivity • Determine the therapeutic index • Assess importance of multiple mediators • Determine pharmacokinetics • Assess safety & toxicology • Set clinical dose range

15. bioinformatics chemistry biochemistry molecular biology electrophysiology genetics immunology histology Pharmacologist: principles of drug action integrated approach skills “.. Unique position to bring specialist knowledge together & make informed judgements on whether or not the new chemical entity has the potential to become a therapeutic agent.” Drug discovery: a multidisciplinary process

16. Future needs • Preclinical knowledge • Proof of concept • Safety & toxicology • “Best guess” for clinical trial “Molecular revolution has led to reemphasis of the central role of in vivo pharmacology in drug discovery”

17. Semester 1: Applied Pharmacology Techniques Quota 24

18. Semester 2: Applied Pharmacology Techniques Quota 20

19. Semester 2: Applied Pharmacology Techniques • Aims are to introduce: • pharmacological techniques used to evaluate the mechanism of action, as well as selectivity, of potential drug candidates both in vitro & in vivo • the theoretical & practical aspects of preclinical drug development from selection of candidate molecule through to Phase I clinical trial • lectures & tutorials to cover the theory & methods involved in each advanced technique which include: • behavioural pharmacology • in vitro preparations of cardiovascular, airway & urogenital tissues • chronic surgical instrumentation • assessment of cardiovascular & autonomic responses in vivo

20. Teaching in vivo pharmacology Man • Integrated pharmacology • Autonomic reflexes, neurohumoral influences • Homeostasis, cardiovascular control • Inflammation, analgesia In vivo In vitro Molecule