Drug Mechanism of Action Two Flashcards
What is the name of the endogenous binding site?
The orthosteric site
What is an alternative name to the orthosteric site?
The endogenous agonist binding site
Is the endogenous orthosteric binding site the only binding site?
No there is also the allosteric site.
What binds to the allosteric site?
Allosteric modulators
When do allosteric interactions occur?
Allosteric interaction occurs between the othrosteric site and any additional conformationally linked site when both sites are occupied by ligands.
What is an allosteric modulator?
Ligands that bind to an allosteric site on the GPRC to modulate the binding and or signalling properties of the othrosteric site
What does the allosteric modulator manipulate?
Affinity and Efficacy.
What is the difference between affinity, Efficacy and potency?
Affinity describes the ability of a ligand to bind to a receptor.
Efficacy is defined by Emax, which is the maximal response able to be produced by a ligand. It also defines if a ligand is an agonist, inverse agonist or antagonist.
Potency is described by EC50, the concentration of drug required to produce 50% of the maximal response. The lower the EC50 the more potent the drug.
What three properties can an allosteric modulator manipulate? and what does this do to the concentration response curve?
Affinity (same Emax but curve is left shift)
Efficacy (increased Emax)
Agonism (Curve shifts upwards)
How can an allosteric modulator alter affinity?
It can increase ligand association rate or decrease ligand dissociation rate (this is more common)
Allosteric inhibition can arise from the opposite of this.
How do allosteric modulators change efficacy?
Allosteric modulators have been found to change efficacy of a ligand regardless of affinity.
i.e Emax increases, but the concentration of agonist to achieve ti remains the same, so the y values increase but x remain remain.
What sort of antagonist would an allosteric modulator be?
Non-competitive antagonist
Describe some of the complicated effects allosteric modulators can have
They can increase affinity and decrease efficacy.
What is the ceiling effect, and how does it influence the maximal capacity of allosteric non-competitive antagonism vs reversible competitive antagonism?
Reversible competitive antagonism has no ceiling effect and you can increase the level of agonist and the level of antagonist will also need increasing to maintain the effects. i.e it can right shift infinitely.
Allosteric antagonist have limited right and left shifts (depending on effects) i.e it can only have so much effect….
Why does the ceiling effect exist?
Simple, allosteric modulators do not compete with other ligands therefore once they have bound all receptors their effects are measured in full - as to work ligand must be present.
Why would we want to target an allosteric site rather than an othrosteric site?
The allosteric site is more likely to be highly selective therefore it is easier to bind to a specific receptor. I.e seratonin has 6 orthosteric receptors. Each of its receptors are similar in order to bind seratonin. However each receptor will have its own allosteric site. Thus a specific receptor can be targeted.
Also there are very few endogenous allosteric modulators.
Whats an example of a non-GPCR with an allosteric site?
Ligand gated ion channels.
I.e Benzodiapines target allosteric sites of ligand gated ion channels.
What therapeutic opportunity does an allosteric binding site provide?
Provide another level of selectivity
May only act when endogenous ligand is present, therefore greater spatial and temporal drug
Ceiling effect of non-competitive antagonist
Stimulatory or Inhibitory effects can be caused by drugs. Naming the major groups of drug targets, list if it is possible to produce either effect?
Receptors - drugs can inhibit or activate
Ion Channels - Drugs can only Inhibit
Carrier Molecules (Transporters) - drugs can only inhibit
enzymes - drugs can only inhibit
Why do Enzymes, transporters as drug targets, only inhibit?
The drug in these instances binds to the orthosteric site, therefore preventing the binding of the endogenous ligand = inhibition of action
What are the four steps of neurotransmission?
Neurotransmitter synthesis
Neurotransmitter Release
Action on receptor
Inactivation
What are the types of inactivation?
Breakdown (Enzyme)
Transportation (away from site of action)
Why must inactivation occur?
To prevent constant stimulation of the post synaptic cell
What are examples of neurotransmitter that is broken down or transported away?
broken down = ACh
Transported away = Seratonin and Dopamine
What is the enzyme that breaks down ACh?
ACh esterase
Can we inhibit ACh esterase?
Yes
What effect does the inhibition of ACh esterase have?
Depends on the nature of inhibition i.e what bonds are formed = duration of inhibition and effect.
List some examples of irreversible AChE inhibitors:
Organophosphate compounds or nerve gases.
An irreversible AChE inhibitor results in?
High toxicity
How does AChE become inhibited?
The compounds form highly stable bonds e.g covalent bonds. Thus making it irreversible often.
How do organophsophates inhibit AChE?
Form phosphorous bonds with AChE which resist hydrolytic cleavage for up to several hours inhibiting all AChE activity, resulting in ACh build up in the synapse and continued ACh function.
what are symptoms of AChE inhibition/ prolonged ACh in the synpase?
Sweating Dimmed Vision Uncontrollable vomiting and defacation Filling of bronchial passage with mucous Bronchial Constriction Paralysis and asphyxiation from respiratory failure
What is the bodies only method to overcome irreversible binding?
To upregulate new receptors
How do reversible AChE inhibitors work?
Only function for a short period of time using non-covalent bonds. Bond type depends on length of effect wanted.
What disorders require a reversible AChE inhibitor?
Disorders characterized by a decrease in cholinergic function.
What would a reversible AChE inhibitor allow?
Increase the duration ACh is available in the synapse, so one molecule can activate multiple receptors
What are two examples of conditions that would require a AChE reversible inhibitor?
Myasthenia gravis and Alzheimers
How do AChE help treat myasthenia gravis?
Myasthenia gravis is an autoimmune disorder characterized by debilitating muscle weakness.
Weakness due to ACh receptor breakdown on the muscular endplate (therefore no innervation of muscle)
Pyridostigmine bromide is mostly used as doesnt cross BBB only works on muscular receptors thus no psychiatric effects.
What AChE inhibitor is used to treat myasthenia gravis?
Pyridostigmine bromide is mostly used as doesnt cross BBB only works on muscular receptors thus no psychiatric effects.
Why is AChE inhibitor used to treat Alzheimer?
Drugs that cross the BBB e.g tetrahydroaminoacridine and Donepezil are used to allow ACh to have extended function in the neural synapses. Therefore easing some memory and language deficits.
Because in Alzheimers brain cell loss results in the loss of cognitive and behavioral function.
What AChE inhibitors are used in alzhiemers?
tetrahydroaminoacridine and Donepezil
whats en example of a transporter that inactivates neurotransmitter?
Seratonin (5HT) transporter.
whats the function of 5HT?
Seratonin re-uptake
Why is seratonin re-uptake essential?
for Sleep, Appetite, memory, sexual behavior, neuroendocrine function and mood.
What does 5HT determine?
Extent and duration of post synaptic receptor activation?
What is the chemical name for seratonin?
5 hydroxytryptophan
What family is the 5HT a part of?
Na and Cl dependent transporters
Describe 5HT’s structure?
12 transmembrane domains
Describe how 5HT functions:
1) Na binds allowing 5HT to bind
2) Cl then binds to allow trans location. Followed by their dissociation.
3) K binds and is trans located out of the cell and dissociates to complete the cycle.
what does SSRI stands for?
Selective Seratonin Reuptake Inhibitors
Whats an example of an SSRI?
Prozac / Antidepressants
What is an effect of an SSRI?
Prevents seratonin reuptake prolonging its action and duration in the synapse.
