Flashcards in Drug Targets Deck (58):
How do most drugs produce and effect?
Most drugs produce and effect by binding to a protein molecule, resulting in a conformational change in the protein.
What are the major drug targets?
The four major drug targets of PROTEINS are:
- Ion Channels
- Carrier Molecules
Do all drugs target receptors?
No, the also target ion channels, enzymes and carrier molecules.
Do all drugs target proteins? If not then what?
No, a Number of ANTITUMOR and ANTIMICROBIAL Drugs act on DNA
What is an existing structure for cell to cell communication?
How many steps are involved in Neurotransmission?
It is a four step process including:
- Neurotransmitter Synthesis
- Neurotransmitter Release
- Action on Receptors
Where can drugs target in the Neurotransmission process?
All the four steps provide a potential target for drug action.
- Neurotransmitter Synthesis
- Neurotransmitter Release
- Action on Receptors
How are neurotransmitters tightly regulated?
They are inactivated at the end of their use by enzymes to break them down and transporters to remove them from the system.
Why are some neurotransmitters broken down or removed from a system?
To allow tight regulation of the receptor mediated event.
What system of receptors are looked at in detail?
What steps are involved in neurotransmitter function of the cholinergic system?
ACh is synthesized and stored in vesicles.
Action Potential travels down the axon and activates Ca channels.
Ca promotes vesicle binding and ejection of ACh into the synaptic cleft.
ACh binds to the receptor and induces a response
ACh is then broken down
How is ACh synthesized?
Choline is taken up into the neuron.
Choline acetyle transferase forms ACh in vesicles.
How is ACh released?
-ACh is packaged in synpatic vesicles by the vesicular ACh transporter
-Vesicles are held in the cytoskeleton by Ca sensitive vesicule membrane proteins
-Action potential reaches the terminal and activates Ca voltage dependant channels
-rapid Ca influx causes vesicle fusion with the membrane and ACh release into the synapse
What inactivates ACh?
ACh Esterase breaks it down
What are two keys sites for drug action of ACh synthesis to down regulate its production?
Choline transporter (rate limiting step in ACh synthesis)
Choline Acetyle Transferase - Enzyme for ACh synthesis.
If a drug were to inhibit these it would in the long term down regulate the ACh production and thus inhibit neurotransmitter function. It would be slow because ACh would still be stored in vesicles and could act even if ACh production had ceased.
What are receptors?
Proteins that specifically recognise a particular neurotransmitter/hormone and upon binding undergo a conformation change leading to activation/inhibition of cell signal.
What are the four main families of receptors?
Ligand gated ion channels
g protein coupled receptors
tyrosine kinase/cytokine receptors
nuclear/steroid hormone receptors
Of the four main families of receptors which ones are membrane bound?
Ligand gated ion channel
tyrosine kinase receptor
Of the main families of receptors if they are not membrane bound then what are they?
The nuclear/steroid receptor is found in the cytoplasm and is therefore said to be intracellular
Where could drugs target in the release process of the cholinergic system?
Bock voltage dependant Ca channels
Block Vessel binding to membrane
All these would result in the fast acting inhibition of the cholinergic system
For the main four classes of receptors what are there effectors?
Ligand gated ion channels = Ion channel
g protein coupled receptors = Channel or Enzyme
tyrosine kinase/cytokine receptors = Enzyme
nuclear/steroid hormone receptors = Gene transcription
What are some examples of molecules that have Ligand gated ion channel receptors?
What are some examples of molecules that have GPCR?
What are some examples of molecules that have tyrosine kinase receptors?
What are some examples of molecules that have nuclear/steroid hormone receptors?
Thyroid hormone receptors
Which of the four main classes of receptors act the fastest and the slowest?
Ligand gated ion channel receptors are the fastest while the Nuclear/steroid hormone receptors are the slowest.
What is noteable about ligand gated ion channel complexes structures?
They are all have multiple sub units
What are three key features of ligand gate ion channels?
Highly selective = Only respond and are activated by specific molecules
Conduct ions through otherwise impermeable membranes = control cell polarity
Select specific ion flow
With regards to ion flow through ligand gated ion channel receptors, how do excitatory and inhibitory flows differ?
An excitatory neurotransmitter will result in flow of positive ions into the cell = depolarisation
Inhibitory neurotransmitter will result in a flow of negative ions into the cell = hyperpolarisation
How many subunits does the nicotinic acetylecholine receptors have?
What are the nicotinic acetylecholine receptors subunits?
What subunits are involved in the binding areas for ACh in nicotinic acetylecholine receptors?
Alpha and beta
Alpha and gamma
What is required for the nicotinic acetylecholine receptors to allow ion flow?
ACh binding to BOTH receptors
How do the nicotinic acetylecholine receptor transmembrane ion channel prevent flow when not activated?
The five M2 helicies are sharpley kinked inwards halfway down the channel forming a constriction.
How do the nicotinic acetylecholine receptor transmembrane ion channels kinks open?
They snap to attention when ACh binds to both receptor sites.
The nicotinic acetylecholine receptor pore is highly selective for ions, how?
The proteins amino acids of the TM2 subunits determine the passage of ions.
What do most excitatory molecules cause ligand gated ion channels to do?
Allow the passage of positive ions such as Na and K into the cell. (depolarisation allowing conduction of AP possible)
Is nicotine excitatory or inhibitory?
How does nicotine function?
The nicotinic acetylecholine receptor, allows nicotine to bind and it causes a mutation of the critical residue allowing the channel of TM2 to allow the passage of anions instead of cations. (change in selectivity)
what are ligand gated ion channel receptors also known as?
What are three neurotransmitters that are targeted by drugs, that act on ionotropic receptors?
What are some drugs that act on ionotropic receptors in place of GABAa and how so?
GABAa is inhibitory, drugs that bind, resulting in a excitatory response instead include:
Benzodiazepines (drug for anxious people)
What are some drugs that act on ionotropic receptors in place of Glutamate and how so?
Glutamate is excitatory, therefore these drugs aim to result in a inhibitory response:
Aiming to use these receptors as anticonvulsants and neuroprotection but hullucination is a common side effect.
What are some drugs that act on nicotinic ionotropic receptors in place of ACh and how so?
Nicotinc receptors are excitotory and the only ligand gated ion channel that responds to ACh. Drugs that result in a inhibitory response include:
Pancuronium (muscle relaxant)
What is essentially the purpose of ligand gated ion channels?
To change cell polarity
How do GPRC function?
Upon activation g protein undergoes conformational change and results in the change secondary messanger concentrations resulting in an array of functions, cell regulation, growth hormone production etc.
What is essential about all receptors?
They are highly selective, especially for GPCR
How many muscunaric GPCR are there?
Since there are five muscunaric receptors how can drug efficacy be a problem?
They can have an effect on all five types of receptors around the body. not good
So the goal now is to make drugs specific to the specific receptor.
With regards to the anatomy of the cholinergic neurotransmission system, what muscunaric receptors are present?
M1 on the post synaptic cleft
M2 on the presynpatic cleft
What is typical of presynpase receptors?
Tend to be Gi linked. (G protein inhibitory)
What does activation of M2 result in, in the cholinergic system?
Inhibition of voltage sensitive Ca channels. Thus decreased neurotransmitter release.(feedback loop)
Are pre and posy synaptic receptors the same?
No they are pharmacolgically different, thus can be targeted by drugs.
List some GPCRs
List some drugs that act on B adrenoreceptors
Propranolol (decreased HR) and Isoprenaline
List some drugs that act on Adenosine receptors
Caffine and Theophylline (bronchiodilator)
List some drugs that act on Muscunaric receptors
Atropine (slows HR)