Drug Targets Flashcards
Name two types of drugs that can act on receptors, and their actions:
Agonists (or inverse agonists)- directly bind and open ion channels or through transduction mechanisms activate/inhibit enzymes, modulate ion channels or lead to DNA transcription.
Antagonists- block endogenous mediators and produce no effect.
How do ion channels provide a drug target and how do they work?
Ion channels sit in the lipid membrane and may either be blocked to produce no ion flow, or modulated to increase or decrease opening probability.
What are the three types of drugs which act on enzymes to produce their effects?
Inhibitors block the normal enzymic reaction.
False substrates lead to abnormal metabolite production.
Prodrugs lead to an active drug being produced.
How may drugs act on transporters to produce their effects?
They may lead to normal transport.
Inhibitors may block transport.
False substrates may lead to accumulation of an abnormal compound.
Receptors serve as recognition sites for specific endogenous compounds or ligands. What are three classes of these compounds, with examples?
- Neurotransmitters e.g. noradrenaline (NA)
- Hormones e.g. adrenaline (released from adrenal medulla and acts on the heart)
- Local hormones/autacoids e.g prostaglandins (released and act upon nearby tissue)
How many binding sites do receptors have?
At least one (often more than 1)
What are ligands, and what two classes can they be?
Chemicals which bind to receptors.
Endogenous e.g. ACh
Exogenous e.g. atropine
What it the difference between specificity and selectivity?
Specificity means that the receptor will bind only one compound.
Selectivity means that the receptor will select which compound it binds based on the shape of the compound and the binding sites on the receptor.
What is affinity?
Affinity is the attraction of a ligand/drug for a receptor. For binding to a receptor to occur the drug and receptor must have affinity for each other.
What is efficacy?
This is the intrinsic activity of the drug which can be between 1 (maximum effect) and 0 (no effect) to describe the strength at which an effect is produced.
In terms of affinity and efficacy, how do agonists and antagonists differ?
Agonists have affinity and efficacy (mimics).
Antagonists have affinity and NO efficacy (blocks).
Name three important features of receptor structure in terms of function:
- Specificity for ligand (including the stereospecificity).
- Verification of receptor family subtypes (sequencing).
- Structure confers functionally important characteristics for intracellular signalling (transduction).
Are drugs totally specific for a receptor family? And what is a consequence of this (example)?
No- this can lead to unwanted side effects such as anti-histamines being drowsy.
What is the difference between receptor families and subtypes?
Receptor families all have 1 endogenous ligand (e.g. histamine, dopamine).
What two properties is drug action dependent on, and what do these mean?
- Drug properties- selectivity for receptor subtypes.
2. Tissue properties- distribution of receptor subtypes throughout the body e.g. histamine.
What are the roles of different family subtypes in relation to histamine?
H1- skin, allergic reactions
H2- stomach acid secretion
H3- CNS, ileum and cardiac tissue, often presynaptic or autoregulatory
This means drugs need to target a specific subtype in order to avoid side effects from other subtypes e.g. drugs targeting H1 may also act on H3 and produce adverse effects in non-target organs.
Define selectivity (of receptors) and give an example of how this can lead to beneficial or adverse effects:
This is the preferential binding to a certain subtype which leads to a greater effect than other subtypes.
This is important in salbutamol which binds to B2 at lungs rather than B1 at heart when treating asthma. Antihistamines are selective for H1 receptors.
A lack of selectivity can lead to unwanted effects, such as fenoterol and propranolol.
What are some of the benefits of selectivity in relation to histamine receptors?
H1 antagonists (antihistamines) can be used for treatment of hayfever and allergy (e.g. chloropheniramine, loratidine).
H2 antagonists can be used for inhibition of gastric acid secretion (e.g. cimetidine).
H3 antagonists used as experimental tools for treating pain and inflammation (target CNS) (e.g. thioperamide).
Describe a situation where there is non-receptor specificity/selectivity:
NSAIDS can lead to problems with ulcers and uncontrolled bleeding. COX II inhibitors are selective for the inducible form of COX which have little effect on the constitutive form (e.g. rofecoxib, celecoxib).
Name the four receptor theories:
- Receptor occupancy theory- drug effect is proportional to the number of receptors occupied.
- Rate theory- drug effect is proportional to the rate of occupancy.
- Two state model- receptors exist in the active or inactive form.
- Floating receptor model- the drug receptor complex may interact with a variety of effectors in the membrane to produce its effect.
Describe the receptor occupancy theory and how this can be represented graphically:
An equilibrium exists between the drug and receptors being together or apart, with the response proportional to the receptor-drug together.
This is a logarhytmic relationship between concentration and fractional occupancy. This produces a sigmoidal relationship with log concentration values, where Ka is the constant which gives 50% occupancy (measure of affinity).
What is meant by ‘receptor plasticity’, and what is it responsible for over time?
Receptor states and populations can be altered by physiological, pharmacological or pathological states to alter the number of receptors.
This plasticity is responsible for the changes that occur in the effectiveness of chronic drugs/endogenous compounds over time e.g. insulin resistance, morphine tolerance etc.
Describe the four situations which arise from the two-state receptor model:
- No ligand- equilibrium favours R (resting state).
- Full agonist- strong preference for R+ (active state)- equilibrium strongly shifted to R+.
- Partial agonist- weak preference for R+- equilibrium partially shifted to R+.
- Antagonist- no preference- equilibrium not shifted, however, this prevents agonist binding.
Name the four receptor families and what they are linked to:
How are these families grouped?
- Ionotropic- linked to ion channels.
- Metabotropic- g-protein coupled.
- Catalytic- linked to kinases (phosphorylating enzymes).
- Nuclear/intracellular-linked to gene transcription.
Families are grouped according to structure and signal transduction system.
What is the general structure of ligand-gated ion channels?
Generally a series of 4-5 subunits which form a pore in the membrane, with an extracellular amino terminal ligand binding domain and an extracellular carboxy terminal.
What is the general structure of G-protein coupled receptors?
Generally have 7 transmembrane spanning domains with two binding sites, one on the extracellular N terminal and one in the receptor itself. There is an intracellular carboxy G-protein coupling domain.
What is the general structure of kinase-linked receptors?
Single transmembrane spanning domain with an extracellular amino binding domain and an intracellular catalytic carboxy domain.
What is the general structure of intracellular receptors?
These have no membrane and have a carboxy teminal binding domain and a DNA binding domain (zinc fingers).
How do ionotropic receptors fucntion?
These act very fast. The binding of the agonist causes a conformational change in the receptor which leads to ion channel opening.
Depending on which receptor is involved, different agonists can can an increase in channel-opening time (nAChR) or an increase in channel conductance (glutamate).
What type of receptor is nACh, and what is its structure?
It is an ionotropic receptor and consists of 5 subunits (2 alpha, 2 beta and 1 gamma), where there are two binding sites between the alpha subunits and the gamma subunit where ACh can bind, causing a change in shape so ions can flow through.
What type of receptor is GABA-A and what is its structure?
It is an ionotropic receptor and consists of 5 subunits. Binding to either the benzodiazepine (diazepam) or barbiturate (pentobarbitone) binding site enhances GABA binding and and increases rate or duration of channel opening.
How do G-protein linked receptors function?
These work fast (but slower than ionotropic receptors). Binding of the agonist causes G-protein activiation leading to opening or closing of an ion channel or the generation of second messengers (e.g. cAMP, IP3) to produce a biological effect.
In the resting state there is no binding of the ligand and a(GDP)-BY is linked. Upon binding of the ligand, a(GDP) links to the receptor and produces GTP while BY links to the target 2, and a(GTP) links to target 1. GTP is then hydrolysed and returns to resting state.
Name the three G-protein coupled receptor families:
Gs (stimulatory), Gi (inhibitory) and Gq.
Name two examples of G-protein linked receptors:
mAChR and adrenoreceptors.
