Lecture 71 - Drugs as Tools

Question 1

What happens to drugs that don’t make it to the clinical setting?

Answer 1

Used as tools to better understand biology

Used as tools for a new drugs discovery process (ie in further research)

Question 2

Outline drug discovery

Answer 2

1. Viable therapeutic area
2. Identiy molecular target
3. Design drug
4. Testing
5. Use in patients

Question 3

What are issues that can arise with identification of target?

Answer 3

Unknown aetiology

Question 4

What difficulties can arise with design of drug?

Answer 4

Full activity of target not well characterised

Question 5

What difficulties can arise with testing?

Answer 5

Potency / Selectivity issues

Question 6

What difficulties can arise with use in patients?

Answer 6

Poor clinical profile:
• pharmacokinetics
• off-target toxicity

Question 7

What difficulties can arise after the drug is on the market?

Answer 7

Competition with another drug

Question 8

How can one recognise failed therapeutics?

Answer 8

Prefix

eg. UK-92,480

Question 9

What was Reserprine previously used for?

Answer 9

Anti-hypertensive

India: ‘insanity’

Question 10

Where is Reserprine derived from?

Answer 10

A plant (Raiwolfia)

Question 11

Describe the mechanism of action of Reserprine

Answer 11

Inhibits transport of dopamine into synaptic vesicles (where they are converted to NA)

Dopamine degraded by MAOs

Sympathetic neurons depleted of NA (and serotonin)

Question 12

Describe the production of noradrenaline

Answer 12

Tyrosine
L-DOPA
Dopamine
- dopamine transported into a synaptic vesicle -
Noradrenaline

Question 13

Is Reserprine a good therapeutic?

Answer 13

No - its affects were too broad

Question 14

What was Reserprine later used for?

Answer 14

As a research tool

Question 15

Describe how Reserprine was used as a research tool

Answer 15

• Examining sympathetic NS actions
• Model for depressive illness & Parkinson’s
• Evidence for monoamine hypothesis of depression
• Role of dopamine in schizophrenia

Question 16

What was the ‘one nerve, one neurotransmitter’ hypothesis?

What is a more accurate hypothesis?

Answer 16

A single neuron can only release on type of neurotransmitter:
• homogenous synaptic vesicle

Each synaptic vesicle contains a number of compounds

Question 17

Describe the GP vas deferens study

Answer 17

GP vas deferens in an organ bath
Stimulation of sympathetic neurons
Bi-Phasic response:
• rapid, short lived contraction
• slower, longer lived contraction

Prazosin added:
• blockage of alpha-adrenoceptors

Stimulated again
• only rapid response seen

Addition of ATP derivate
• response completely wiped out

Question 18

What was the conclusion of the GP vas deferens study?

Answer 18

ATP: rapid response
NA: longer contractile response

Co-transmission: nerves can release more than one neurotransmitter

Question 19

What is the hypothesis of co-transmission?

Answer 19

One nerve releases multiple neurotransmitters

Question 20

What is purinergic transmission?

Answer 20

Purines, such as ATP, acting as neurotransmitters

• instant response

Question 21

How was Prazosin used as a tool?

Answer 21

Lead to co-transmission hypothesis

Question 22

What is the effect of clonidine?

Answer 22

a-adrenoceptor agonist

Question 23

Describe the clonidine study

Answer 23

Heart in an organ bath
• Clonidine introduced into organs bath
• Reduced heart rate

Exogenous NA added
• clonidine now had no effect
–> not a beta blocker then

Question 24

Describe the function of the pre-junctional alpha-2 adrenoceptors

Answer 24

• NA acts on the pre-junctional receptors on a-2 adrenoceptors
• Negative feedback on pre-synaptic cell
• Reduced NA release

Question 25

What were the conclusions of the clonidine study?

Answer 25

Clonidine only acts on endogenous NA, not NA

–> revelation of pre-junctional receptors
• drugs modulating the nervous system

Question 26

Which three drugs are given as examples of how failed therapeutics were used as tools?

Answer 26

Reserprine
Clonidine
Prazosin

Question 27

Describe what happened with Isabel Dinoire

Answer 27

First partial face transplant
Initially:
• difficultly occluding the lips
After a few months:
• symmetic
• closing of the lips

Question 28

What difficulties are there with organ transplantation?

Answer 28

Host will launch an immune response against the transplanted organ

Recipient will undergo lifelong immunosuppression

Question 29

What were cyclosporins used for?

Answer 29

Immunosuppression

Question 30

Describe transplant rejection

Answer 30

• Self-antigens of the foreign organ recognised as foreign by T cells
• MHC II + antigen recognised by TCR
• IL-2 produced
• T cell effector functions, immune response

Question 31

What is the target of cyclosporin?

Answer 31

Calcineurin

Question 32

What is the function of Calcineurin?

Answer 32

Phosphatase
• removes phosphate from NFAT

NFAT
• a transciprtion factor
• transcription of IL-2 gene

Thus, IL-2 production is activated by Calcineurin

Question 33

What are the immunophilins?

Answer 33

Cyclophilin: binds cyclosporin
FKBP: binds tacrolimus

Question 34

What was the outcome of Cyclosporins and Tacrolimus?

Answer 34

Discovery of the immunophilins
Understanding of action of calcineurin

• understanding of T cell activation in the immune response

Question 35

What about paracetamol?

Answer 35

After many years of use, the mechanism of action that produces the analgesic effect in unclear

Question 36

What is the role of Lyn

Answer 36

Src kinase

Role in allergy, IgE response

Question 37

What is PP2?

Answer 37

Potent and selective inhibitor of Src kinases, including Lyn

• doesn’t just inhibit Lyn
• also has affects on other Src kinases at different concentrations