Receptors Flashcards
Which opiate receptor has the highest affinity for morphine
Mu receptor
What are endorphins and enkephalins
Endogenous ligands for opiate receptors
Drug definition
A known chemical structure which when administered to a living organism produces a biological effect
Types of drugs
Synthetic chemicals, plant chemicals and biopharmaceuticals
What is a biopharmaceutical
Something that is made from DNA
Medicine definition
A chemical preperation that contains one or more drugs admnistered to produce a therapeutic effect
What other compounds do medicines contain
Excipients, stabilizers and solvents
Examples of biopharmaceuticals
Proteins (could be endogenous), engineered proteins, antibodies, oligonucleotides, gene therapy and regenerative medicine
What is the first generation of biologics
Copies of endogenous proteins produced by recombinant DNA technology
What is the second generation of biologics
Engineered proteins to improve antibodies
Benefits of biologics
Your body doesn’t accept them but treats them as another human antibody
What can biologics be used for
Treating cancer and immune diseases
What does MAB mean at the end of a drug name
Monoclonal antibody
What does Humira do
Recognises an inflammatory mediator known as TNF alpha
How much does Humira cost
14,000 million
What is the basis of the Moderna vaccine to treat COVID
Injecting people with mRNA that codes for a protein
What is Pharmacoeconomics
Considers the cost benefit of a drug
What kind of proteins do drugs exert their actions on
Receptors, enzymes, transporters, ion channels
What macromolecules other than proteins can drugs exert their actions on to
Antibiotics and antimicrobials
How are receptors classified
Structure, pharmacology, signalling mechanisms
What can increasing the dose of a drug do and why
Lead to unwanted side effects because no drug is 100% selective and specific
What can malfunction and loss or receptors lead to
Disease
What is an agonist
A drug that causes the receptor to switch on and bring about a change within the cell once bound to
What is an inverse agonist
When bound to a receptor, they reduce signalling to that receptor
What are antagonists
When bound to receptor, they do nothing and blocks the receptor from carrying out its action
What is morphine an agonist for
Mu receptor
What are Mu receptors
They are g-coupled receptors in the location of the brain that processes pain and reward pathways
What are blockers (drugs) and example
They enter the pore of the channel and prevent ions from moving through them. For example, Lidocaine
What are modulators (drugs) and example
They modify the way the channel behaves, can open more or less. For example, Valium
What does Lidocaine target
sodium channels that send information to the brain when you have a painful incident
What do enzyme inhibitors do and example
The normal reaction is inhibited. For example, aspirin
What do enzyme false substrates do
The molecule enters into the enzyme to produce something that is inactive/ abnormal metabolite is produced
What do prodrug enzymes do
Active drug is produced
Examples of transporter drugs
Prozac and digoxin
What does Colchicine do
Disrupts the cytoskeleton and inhibits the invasion of immune cells into the inflamed joint
What does Paclitaxel do
Targets and prevents the diasembly of microtubules
What does Paclitaxel do
Targets and prevents the disassembly of microtubules to stop cell division
Main side effects of opiate
Chronic constipation and respiratory issues
Why is knowing where the receptor is in the body important
Helps us predict drug affects
Examples of agonists for the MU-receptor
Morphine, heroin, methadone, codeine, fentanyl, beta-endorphins
What is a ligand
Any molecule that binds to the receptor
Examples of antagonists for the MU- receptor and what does it do
Naloxone, stops heroin activation
What are the 4 types of receptor
Ligand- gated ion channels, g- coupled protein receptors, kinase linked receptors, nuclear receptors
What is the largest class of receptor
G- coupled
What is kinase
Any protein which has enzymatic activity that adds phosphate to another protein
What are the fastest receptors
Ligand gated
Slowest receptors
Nuclear (take a couple of hours
What is the basic mechanism for ligand gated ion channels to open
Ions flow through aqueous pore which is opened when neurotransmitter/ agonist binds. Flow of ions leads to changes in membrane potential causing action potentials to fire
Examples of ligand gated ion channels and the number of transmembrane domains
Nicotinic, 4
Glutamate, 3
P2XR, 2
What happens when agonist binds to g-coupled receptors
They signal the change by activation of a g protein
What are the g protein subunits in g coupled receptors
Alpha, beta and gamma
What is the alpha subunit less attractive to (what happens next)
GDP so has a greater affinity to GTP. When GDP comes off GTP comes on
What happens to the alpha subunit over time
It becomes a nuclear kinase
What does activation of kinase receptors lead to
Changes in transcription
What are cytokine receptors useful for
Regulate within the nucleus
What is an important feature of nuclear receptors
They bind directly to DNA to regulate the transcription of genes
What percentage of the mammalian genome is regulated by nuclear receptors
1%
What is an autoimmune disease
Makes an antibody to itself and the target can be a receptor
What is Myasthenia Gravis
Antibodies to nicotine acetylcholine receptors involving muscle contractions
What is Gravis disease
Where a thyroid receptor is targeted leading to high metabolic rate, increased skin temperature
What can epilepsy be caused by
A mutation leading to increased stimulus to a receptor
What do mutations in the beta- 2 adreno receptors lead to
Means that inhalers don’t work
What is affinity
A chemical property that defines how likely they are to come together
What is the constant for the forward and backward reaction
K+1 and K-1
What is how good a molecule is at fixing a receptor governed by
efficacy
What is the number of receptors that are occupied by a drug in one point of time determined by
affinity
what is KD
A constant that defines the affinity of a drug for that receptor
What is the forward rate of a reaction defined by
The forward rate constant multiplied by the concentration of the agonist and concentration of receptors
What is the order of reaction for the forward rate and why
Second order because it depends on the concentration of two types of molecules
What is the reverse rate of reaction equation
k-1[AR]
What is the dissociation constant equal to
The reverse reaction divided by the forward reaction
What is KD a direct measurement of
affinity
What is occupancy governed by
Affinity
Equation for occupancy
number of receptors occupied/ total number of receptors
What does occupancy vary between
0 (no drug present) and 1 (all receptors occupied)
How do we measure affinity
Radioligand binding assay
What are the steps for measuring receptor affinity
Mix these two together, incubate them and filter the sample so only thing left is the receptors bound radioligand, then analyse the data
what are some considerations for measuring receptor affinity
Controlling the temperature so proteins aren’t digested
Adding antioxidants in case the molecules released from the cells are oxidisable
Free radical scavenger to stop degradation
Avoiding light
What must the radioligand be in measuring receptor affinity
Must be biologically active and pure chemically
Advantages of using hydrogen in measuring receptor affinity
Won’t cause issues to the structure, affinity will be maintained
Powerful radioactive substance
Long half life
Disadvantages of using hydrogen in measuring receptor affinity
Specialised labs required, labelling is expensive and difficult
Advantages of using iodine in measuring receptor affinity
Similar size of aromatic amino acids
Chemistry involved is straight forward
Disadvantages of using iodine in measuring receptor affinity
Easily degradable, more radical change in structure of the molecule
How do you separate the bound from the free in measuring receptor affinity
Wash away the none bound drug
What is non-specific binding
The ligand will bind to other things in addition to the receptors e.g. plastic test tube
How to stop non-specific binding
Setting up two test tubes in parallel, add a known concentration of radioactive drug to one and a huge excess of non-radioactive drug to the other
Non-radioactive drug will outcompete radioactive drug
Subtract non-specific binding from the total to get the specific binding
What does affinity give us an indication of
What levels, of drug are needed in the body to have a therapeutic effect and a way of identifying and defining the type of receptor
What kind of relationship do we get between the concentration and the amount of binding
Sigmoidal
What happens to the values in a sigmoidal relationship
They plateau, shows 100% occupancy
What does 100% occupancy mean
100% of the receptors in that tissue are occupied by that drug
What is the Langmuir equation
Bound= bmaxXa/ (Xa + KD)
The concentration that occupies 50% of the total number of receptors present gives us a direct measure of what
KD
What does a low KD show
High affinity
What can the drug Pirenzepine distinguish
Distinguishes between the subtypes of muscarinic receptora
