Lecture 71 - Drugs as Tools Flashcards
What happens to drugs that don’t make it to the clinical setting?
Used as tools to better understand biology
Used as tools for a new drugs discovery process (ie in further research)
Outline drug discovery
- Viable therapeutic area
- Identiy molecular target
- Design drug
- Testing
- Use in patients
What are issues that can arise with identification of target?
Unknown aetiology
What difficulties can arise with design of drug?
Full activity of target not well characterised
What difficulties can arise with testing?
Potency / Selectivity issues
What difficulties can arise with use in patients?
Poor clinical profile:
• pharmacokinetics
• off-target toxicity
What difficulties can arise after the drug is on the market?
Competition with another drug
How can one recognise failed therapeutics?
Prefix
eg. UK-92,480
What was Reserprine previously used for?
Anti-hypertensive
India: ‘insanity’
Where is Reserprine derived from?
A plant (Raiwolfia)
Describe the mechanism of action of Reserprine
Inhibits transport of dopamine into synaptic vesicles (where they are converted to NA)
Dopamine degraded by MAOs
Sympathetic neurons depleted of NA (and serotonin)
Describe the production of noradrenaline
Tyrosine L-DOPA Dopamine - dopamine transported into a synaptic vesicle - Noradrenaline
Is Reserprine a good therapeutic?
No - its affects were too broad
What was Reserprine later used for?
As a research tool
Describe how Reserprine was used as a research tool
- Examining sympathetic NS actions
- Model for depressive illness & Parkinson’s
- Evidence for monoamine hypothesis of depression
- Role of dopamine in schizophrenia
What was the ‘one nerve, one neurotransmitter’ hypothesis?
What is a more accurate hypothesis?
A single neuron can only release on type of neurotransmitter:
• homogenous synaptic vesicle
Each synaptic vesicle contains a number of compounds
Describe the GP vas deferens study
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
What was the conclusion of the GP vas deferens study?
ATP: rapid response
NA: longer contractile response
Co-transmission: nerves can release more than one neurotransmitter
What is the hypothesis of co-transmission?
One nerve releases multiple neurotransmitters
What is purinergic transmission?
Purines, such as ATP, acting as neurotransmitters
• instant response
How was Prazosin used as a tool?
Lead to co-transmission hypothesis
What is the effect of clonidine?
a-adrenoceptor agonist
Describe the clonidine study
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
Describe the function of the pre-junctional alpha-2 adrenoceptors
- NA acts on the pre-junctional receptors on a-2 adrenoceptors
- Negative feedback on pre-synaptic cell
- Reduced NA release
What were the conclusions of the clonidine study?
Clonidine only acts on endogenous NA, not NA
–> revelation of pre-junctional receptors
• drugs modulating the nervous system
Which three drugs are given as examples of how failed therapeutics were used as tools?
Reserprine
Clonidine
Prazosin
Describe what happened with Isabel Dinoire
First partial face transplant Initially: • difficultly occluding the lips After a few months: • symmetic • closing of the lips
What difficulties are there with organ transplantation?
Host will launch an immune response against the transplanted organ
Recipient will undergo lifelong immunosuppression
What were cyclosporins used for?
Immunosuppression
Describe transplant rejection
- 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
What is the target of cyclosporin?
Calcineurin
What is the function of Calcineurin?
Phosphatase
• removes phosphate from NFAT
NFAT
• a transciprtion factor
• transcription of IL-2 gene
Thus, IL-2 production is activated by Calcineurin
What are the immunophilins?
Cyclophilin: binds cyclosporin
FKBP: binds tacrolimus
What was the outcome of Cyclosporins and Tacrolimus?
Discovery of the immunophilins
Understanding of action of calcineurin
• understanding of T cell activation in the immune response
What about paracetamol?
After many years of use, the mechanism of action that produces the analgesic effect in unclear
What is the role of Lyn
Src kinase
Role in allergy, IgE response
What is PP2?
Potent and selective inhibitor of Src kinases, including Lyn
- doesn’t just inhibit Lyn
- also has affects on other Src kinases at different concentrations
