Drug discovery techniques - a specialist course for undergraduate pharmacologists

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Drug discovery techniques - a specialist course
for undergraduate pharmacologists
James A. Angus Christine E. Wright
Department of Pharmacology University of
Melbourne Victoria 3010 Australia
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2000 in vivo practical teaching Australia NZ
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Systems covered by practicals
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Techniques used by students
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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

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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

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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

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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

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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

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The fall rise of in vivo pharmacology- In Vivo
Pharmacology Training Group TiPS 23 13-18,
2002
Disease In vivo experiments
Hypertension ganglion blockers
bethanidine
guanethidine
clonidine
ACEI, captopril
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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 some in 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

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

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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

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Drug discovery a multidisciplinary process

• 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.

• bioinformatics
• chemistry
• biochemistry
• molecular biology
• electrophysiology
• genetics
• immunology
• histology

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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

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Semester 1 Applied Pharmacology
Techniques Quota 24
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Semester 2 Applied Pharmacology
Techniques Quota 20
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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

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Teaching in vivo pharmacology
Man
In vivo
In vitro
Molecule

• Integrated pharmacology
• Autonomic reflexes, neurohumoral influences
• Homeostasis, cardiovascular control
• Inflammation, analgesia