Drug Targets Flashcards
What is the source of penicillin (antibiotic)?
Microorganism
Two hormonal drugs that are from chemical modification.
Ethinyl Estradiol
Prednisolone
Two anti-cancer drugs that are chemically modified.
6-mercaptopurine
6-thioguanine
What is the source of Simvastatin (an HMG-CoA reductase inhibitor)?
Chemical synthesis
Name two drugs that were created due to chance?
Anti-depressants
Cisplatin
Name two drugs from plants/herbs.
Opium Poppy
Foxglove
What are the two types of name a drug can have?
Generic - related to structure/source. This is preferred and has a lower case letter at beginning. Often have similar sounding endings. Can vary between countries.
Brand - marketing name by drug company. Capital letter at start. They can change over time and can vary from country to country.
What is the most common drug target (which is a protein)?
Receptors
What are the 4 common drug targets that are PROTEINS?
- Receptors
- Enzymes
- Ion Channels
- Transporter molecules
What are 2 drug targets that are NOT proteins?
- DNA/RNA
2. Lipids
What is pharmacodynamics?
What a drug does to the body. It binds to a particular site in the body to create an effect.
What are the 2 ways in which a drug can effect a receptor?
- Agonist/Inverse Agonist - mimics
2. Antagonist - Prevents. Endogenous mediators blocked, so there is no effect produced.
What are the 2 ways in which a drug can effect ion channels?
- Blockers - permeation blocked.
2. Modulators - Inc. or dec. opening ability - alters frequency and duration of channel opening.
What are the 3 ways in which a drug can effect an enzyme?
- Inhibitor - normal reaction inhibited.
- False Substrate - Abnormal metabolite produced.
- Prodrug - Active drug produced (codeine -> morphine in body)
What are 2 ways in which a drug ca effect transporters?
- Inhibitor - transport blocked as it binds to protein.
2. False substrate - abnormal compound accumulated.
Chemicals which bind to receptors are called ___ .
Ligands
What is efficacy?
The ability to create a signal (intrinsic activity). Drugs have efficacy or they don’t. Those that don’t, bind and block the receptor.
Maximum effect = 1
No effect = 0
What is affinity?
Attraction of ligand (drug) to receptor.
In terms of efficacy AND affinity, what do agonists have?
Affinity and efficacy.
In terms of efficacy AND affinity, what do antagonists have?
Affinity and NO efficacy.
True or false.
“No drug is totally specific for a receptor family.”
True. This can lead to unwanted side effects (antihistamines).
What is a ‘Family’ of receptors?
One endogenous ligand. (Dopamine, Histamine, etc)
What is a ‘Subtype’ in receptors?
A slight variation in structure of the endogenous ligand.
Where are H1, H2 and H3 (histamines) located in the body?
H1 - skin (allergic reactions)
H2 - Stomach acid secretion
H3 - CNS, ileum and cardiac tissue. It is widespread so is a less desirable target.
What is the effect of Salbutamol?
It is selective to the Beta-2 receptors in the lungs, acting as an agonist, causing smooth muscle to relax. It minimally targets Beta-1 receptors (in the heart) which is good as it could lead to tachycardia.
Lack of selectivity -> unwanted side effects!!
What are the benefits of histamine selectivity?
H1 antagonist - antihistamine
H2 antagonist - stop gastric acid secretion
H3 potentially for treating pain/inflammation
What do NSAIDs do?
inhibit cyclo-oxygenase but problems with ulcers and uncontrolled bleeding.
What do COXII inhibitors do?
Selective for inducible form of cyclo-oxygenases. Little effect on COXI (constitutive form).
What does COXI do?
Maintains mucosa
What does COXII do?
Inflammation.
E.g. rofecoxib, celecoxib
What is the receptor occupance theory?
the more drug, the greater the effect. An equilibrium exists.
Fractional occupancy - logarithmic and sigmoidal.
What is rate theory?
The faster the binding, the stronger the effect.
What is the two state model?
Receptors are active or inactive.
Floating receptor model?
Receptor can cause different signals depending on it’s exposure.
What is receptor plasticity?
States and populations of receptor can alter. This is largely responsible for changes that occur in effectiveness of chronic drug over time.
E.g. insulin resistance, tolerance
If there is no ligand present, drug prefers ____ ____? (2 state model)
Resting state.
If there is FULL agonist, drug prefer___ ___? (2 state model)
Activated state. Efficacy of 1.
If there is a PARTIAL agonist, drug prefers ____ _____? (2 state model)
Weak towards activated AND resting state. Efficacy between 0 and 1.
If there is an antagonist present, drug prefers ____ _____? (2 state model)
Resting state.
What are the 4 receptor family types?
- Ionotropic (ion channels)
- metabotropic (G-protein coupled)
- catalytic (kinases)
- Intracellular (gene transcription)
In terms of the time it takes to occur, Ionotropic receptors are ___ .
Very fast (milliseconds)
In terms of the time it takes to occur, metabotropic receptors are ___ .
Fast (but not as fast as ionotropic receptors)
Seconds.
In terms of the time it takes to occur, catalytic receptors are ___ .
Slow (hours)
In terms of the time it takes to occur, intracellular receptors are ___ .
Slow (hours) BUT they are long lasting.
What happens in the cell due to ions flowing in via ionotropic receptors?
Depolarisation or Hyperpolarisation. The ligand binding causes a conformational change in the receptor, leading to the channel opening.
What happens in the cell when ions flow through an ion channel and activate G-protein coupled receptors?
There is a change in excitability and second messengers (cAMP, IP3, DAG) are produced, causing protein phosphorylation.
What happens in the cell when a catalytic receptor is activated?
Protein phosphorylation occurs, effecting and inducing gene transcription and thus protein synthesis. Ligand is NOT lipid soluble.
How is an intracellular receptor activated?
A lipid soluble ligand passes through the cell membrane, entering the cytoplasm, then nucleus, then it binds to the intracellular receptor. Gene transcription is effected and thus protein synthesis.
Give an example of an ionotropic receptor.
nAChR, GABAa
Give an example of a metabotropic receptor.
mACh, adrenoreceptors
Give an example of a catalytic receptor.
Cytokine receptors, growth factors, hormones
Give an example of an intracellular receptor.
Oestrogen receptor, steroid hormone receptors
What is the general structure of an ionotropic receptor?
- 1 subunit of 4 or 5 transmembrane proteins that form a pore
- Binding domain
What is the general structure of a metabotropic receptor?
- 7 transmembrane spanning domains
- 2 binding sites (in membrane and extracellular)
- G-protein coupling domain that determines the type of G-protein and function
What is the general structure of a catalytic receptor?
- SIngle transmembrane protein
- Binding domain
- catalytic domain
What is the general structure of an intracellular receptor?
- Binding domain
- DNA-binding domain (“Zinc fingers”)
- no membrane
- once receptor is bound, it travels to nucleus and binds to DNA.
nACh has what effect on the nAChR ionotropic receptor?
Increase in channel OPENING time.
Glutamate has what effect on ionotropic receptors?
Increase in channel CONDUCTANCE.
What is the structure of a nACh receptor? (Ionotropic)
- 5 subunits (2 alpha, 2 beta, 1 gamma)
- 2 ACh binding sites
- Alpha helices pinch together, forming a gate
What is the structure of a GABAa receptor? (Ionotropic)
- 5 subunits
- GABA binding sites
- benzodiazepines and barbiturates where ligand can bind, enhancing binding of GABA ligand. This would increase rate OR duration of channel opening, letting Cl- ions pass through.
What are the 3 G-protein families?
Gs (stimulatory), Gi (inhibitory), Gq
What are protein kinases?
Enzymes that attach phosphate groups to proteins.
E.g. PKA, PKC
What is the name of different G-protein receptor complexes allowing different G-protein coupled receptors to exert opposing effects on the target enzyme?
Bi-directional control (e.g. both Gs and Gi used). It helps to create balance and is a graded response. If one side is disrupted, the body can counter act this with the other side.
What does Gq activate?
Phospholipase C
What does Phospholipase C do?
Converts PIP2 -> DAG and IP3 (2nd messengers). In smooth muscle cells, it is involved in facilitating muscle contraction.
What does IP3 do?
Binds to IP3 gated Ca2+ channels, inducing calcium ion release from the endoplasmic reticulum. The calcium ions activate PKC.
What does DAG do?
It binds to PKC (activated by calcium ions) then it phosphorylates subsequent substrates.
What does cAMP bind to?
What does DAG bind to?
PKA, PKC
Describe the transduction of the catalytic receptors.
dimerisation of receptors -> autophosphorylation of tyrosine residues -> phosphotyrosine residues accept SH2 domain proteins -> controls cell function
What are catalytic receptors mainly used for?
Cell growth and differentiation.
What 2 important pathways are to do with catalytic receptors?
- Ras/Raf/MAP kinase (cell differentiation)
2. Jak/Stat (inflammation) - when Stat is phosphorylated, dimer is formed.
What do intracellular receptors bind to?
Highly conserved regions of DNA (in the nucleus) that are attached to ligand-binding domains and transcriptional control domains.
When hormone is bound to LBD, inhibitor releases from LBD (in cytosol) and goes into nucleus, altering gene transcription.
What is the difference between concentration and dose?
Concentration - isolated system in solution with KNOWN amount of drug.
Dose - Per body weight: When drug is ingested by the system.
What is the purpose of an organ bath?
Tissue-organ baths are used to maintain the integrity of the tissue for several hours, in a temperature-controlled environment, while physiological measurements are performed.
What does EC50 mean?
The effective concentration that causes 50% of the maximal effect. The lower the EC50, the more potent the agonist is. It is a measure of agonist potency
What is Emax?
The maximal effect (at 100%)
What is pD2?
-log10[EC50]. It is the opposite to EC50. The higher the pD2, the more potent the agonist is. It is the measure of agonist potency.
What is ED50?
The effective dose that produces 50% of the maximal effect.
If EC50 = 1 x 10-7, what is the value of pD2?
7
What is IC50?
Inhibitory concentration that produces 50% of the maximum agonist response. (antagonism)
What is competitive reversible antagonism?
The antagonist competes directly with the agonist for binding to the receptor.
What shift in the concentration-response curve will competitive reversible antagonism create?
A parallel rightwards shift.
What is the spare receptor theory?
With a low concentration of antagonist, you may be able to bind some (competitively) but still have enough (‘spare’) receptors to obtain the maximal response by the agonist. It is harder for the agonist to bind though.
What is pA2?
The -log concentration of antagonist which causes a two-fold shift in the concentration-response curve. The higher the number, the more potent the antagonist, thus a lower concentration is needed.
How do you calculate pA2?
pA2 = pAx + log(x-1)
-x = EC50 (presence of antag) / EC50 (absence of antag)
pAx = -log concn (M) of antagonist
What is competitive reversible antagonism?
Antagonist competes directly with the agonist for receptor binding but with a greater affinity - normally COVALENTLY (can never overcome this with more agonist).
Causes a non-parallel rightwards shift of the concentration-response curve.
What is the potency measure of competitive irreversible antagonism?
pD2’
What is non-competitive antagonism?
They do NOT bind to the same receptor of the agonist so don’t alter agonist-receptor binding. Instead, they interfere with the cascade of events initiated by agonist-receptor binding (SIGNAL TRANSDUCTION PATH) –> Calcium channel blocker.
Non-parallel rightwards shift with depression in concn-response curve.
What is the potency measure of non-competitive antagonism?
pD2’
True or false. The more concentrated the non-competitive antagonist, the more ‘down’ the response.
True. You have a lot more of a preventer, so a lot less response.
What is Physiological antagonism?
Two agonists bind to 2 different receptors and have opposing effects on same tissue. Helps maintain control.
Describe Partial Agonists.
They do not yield a maximal response. They have affinity, but efficacy is <1. They can act as antagonists to full agonists.
In the concentration-response curve, partial agonists as antagonists produce what key feature?
A cross over point. The effects of the drug alone vs with the partial agonist add together, creating a bigger response than agonist by itself.
What is an inverse agonist?
“Constitutive Activity”. Some receptors produce signals on its own, without a ligand binding, and the inverse agonist binds to switch it OFF.
Negative efficacy.
It has the same binding as a reversible antagonist.
What is homologous desensitization? (metabotropic receptors)
Agonist binding not affected but unable to activate adenylate cyclase. Due to phosphorylation of a single serine residue by BARK.
Heterologous Desensitization?
Affects PKA and PKC.
What is the BARK mechanism of action?
The binding of one agonist desensitises the binding to that agonist to the receptor. No signal produced.
What is receptor population changes?
Either up or down regulation of the receptors.
Chronic agonist administration can lead to what?
DOWN regulation of receptors available for stimulation.
Chronic antagonist administration can lead to what?
UP regulation of receptors available.
What is the clinical significance of tolerance?
Down-reg necessitates an increase in drug dose to produce the same effect. This can have undesirable side effects as the drug can bind to other unwanted targets.
What are ACE inhibitors used for?
Treating Hypertension. Prevents ACEII forming, so no vasoconstriction.
What does NSAID inhibition of COXI and COXII lead to?
Dec. inflammation -> dec. pain -> dec. fever
Side effect: gastric mucosa affected
Name the 2 selective COXII inhibitors
Rofecoxib and Celecoxib
- -> Safer (GI Bleeding)
- -> inc. risk of heart attacks
What does Fluoxetine do?
It has an anti-depressant effect. Reuptake is the predominant synaptic removal mechanism for 5HT. Blocking 5HT uptake protein so there are increased levels of 5HT in the synapse.
Depression is thought to come from low 5HT, so increase it.
How do local anaesthetics prevent the passage of pain signals?
Na+ ion channel blockers
