Week 1 Part 2 Flashcards
What are some clinically useful partial agonist?
- Buprenorphine
2. Varenicline
Define ligand
any chemical which combines with a receptor
Ligand binds to recognition site of receptor
- agonist bind to recognition site
2. change conformation - opening/closing of relevant ion channel
What is the direction of ion movement dependent on?
concentration/electrochemical gradient
What happens to the target cell?
nature of the ion
not all ion channels are created equal
sodium floods in
depolarisation
chloride floods in
hyperpolarisation
Define affinity
Tenacity by which a drug binds to its receptor
What does ligands reside at?
minimal energy within a binding locus of a protein
What is the binding affinity influenced by?
non-covalent intermolecular interactions
e. g.
1. Hydrogen bonding
2. Electrostatic interactions
3. Hydrophobic and van der waal forces between 2 molecules
The higher the affinity
The lower this concentration will be
What is binding affinity measured and reported by?
Equilibrium dissociation
What is equilibrium dissociation used for?
Evaluate and rank order strengths of bimolecular interactions
The smaller the KD value
The greater the binding affinity of ligand for its target
What is KD?
a constant between free drug conc and free receptor conc
What happens if you increase the conc of drug?
- shift equilibrium over to right
2. increase in drug-receptor complex
What is the equation for KD?
Free drug [D] + unbound receptor [R] divided by drug-receptor associated complex [DR]
What yields a low KD value?
The numerator of equation will be low
The denominator will be high
Define antagonist
Blocks or dampens a biological response by binding to and blocking a receptor
Define agonist
A ligand that binds to receptor and alters receptor site - result in a biological response
What can receptor antagonist be?
- Competitive
- Non-competitive
- Reversible
- Irreversible
What is a reversible antagonist?
Binds non-covalently to the receptor
Can be washed out
What is irreversible antagonist
Bind covalently to the receptor and cannot be displaced by either competing ligands or washing
What is competitive antagonist?
Bind to the same site as agonist and blocks the agonists action
What is non-competitive antagonist?
Bind to allosteric site on the receptor to prevent activation of receptor
What is example of competitive antagonist?
- simple competitive e.g. nanitidine
2. Pseudo-irreversible slowly dissociating e.g. alosetron
What is example of non-competitive?
- Irreversible: chemically modifies receptor e.g. phenoxy-benzamine
- Allosteric e.g. b-carbolines (BDZ receptor)
- Functionl: acts as a second receptor
What are examples of clinically useful reversible competitive antagonist?
- Ondansetron
- Carvedilol
- Naloxone
What is used to block endogenous agonist?
- Ondansetron (Zofran)
2. Carvedilol (Eucardic)
What is Ondansetron?
- HT-3 receptor reversible competitive antagonist
2. inhibit vomitting
What is Carvedilol?
- Beta1 selective adrenoceptor reversible competive antagonist
- treatment of hypertension
What is used to block exogenous agonist?
- Naloxone
- opioid receptor competitive antagonist
- reverse opioid induced respiratory depression/overdose
What is EC50?
drug concentration producing 50% of a maximal effect
When is there an equilbrium?
Agonist and antagonist competing for a target site
What can restore agonist occupancy?
Raising agonist concentration
What happens when there is an increased agonist concentration?
- increase in fractional occupancy
2. magnitude of functional response is seen
What doesnt antagonist have?
efficacy
- need a suitable agonist
- action can be inhibited by the antagonist of interest
What can antagonist potency be expressed in?
PA2 value
Define PA2?
Negative logarithm of molar concentation of antagonist which will reduce the response of a tissue
What is an advantage of non-competitive inhibitor?
Duration of action is dependent on the rate of turnover of receptor molecules
What is disadvantage of non-competitive inhibitors?
Overdose
What is H+/K+ ATPase?
Proton pump of the stomach
Exchanges H+ for K
Where is H+/K+ ATPase found?
Apical membrane of parietal cells
What is parietal cells?
Highly specialised epithelial cells located in inner lining of stomach called gastric mucosa
How is H+/K+ ATPase activated?
Indirectly by gastrin that causes ECL cells to release histamine
What does histamine do?
Bind to H2 receptors on the parietal cells
Activate CAMP-dependent pathway
Where is K+ recycled from?
Canaliculus (small passageway) into the cytoplasm by K+ channels in apical membrane
Describe mode of action of Omeprazole?
- Absorbed by GI tract into blood
- At PH7 omeprazole is not charged and can cross cell membrane
- In acid enviroment of secretory canaliculus - omeprazole is protonated and therefore trapped so concentration increases
- Omeprazole inactive on protonation converts to active sulfenamide - reacts convalently with H+/K+ ATPase and inhibits activity
- Resumption of acid secretion requires new synthesis of H+/K+ ATPase
- Half life of Omeprazole is ~18 hours
What does G protein bind to?
guanine nucleotide GDP and GTP
What are the 3 different subunits associated with inner surface of plasma membrane and transmembrane receptors?
- Ga
- GB
- GY
What happens in the inactive state?
Ga has GDP in its binding site
What happens when a hormone or other ligand bind to associated GPCR?
Allosteric change takes place in the receptor
causes allosteric change in Ga causing GDP to leave and be replaced by GTP
What does GTP activate?
GA causing it to dissociate from GbGY
What does activated Ga activate?
Effector molecule
what does morphine mimic?
Endogenous enkephalin
Define potency
The amount of drug required to produce a given effect
Define efficacy
The degree to which an agonist evokes a cellular response
What does intrinsic activity refer to?
Effect of agonist at the receptor itself, rather than overall effect on tissue
Define EC50
the molar concentration of an agonist that produces 50% of maximal possible effect of that agonist
Define pEC50
the negative logarithm to the base 10 of EC50 of an agonist
What is pEC50 useful for?
- compare potencies of drugs
2. estimate margin of safety, relative to other actions of drug
What does potency depend on?
- Drug factors - efficacy and affinity
2. System factors - receptor number and efficiency of coupling
What can system factors cancel out?
Differences in drug factors
What happens as the concentration of drug is increased?
Full agonist will go up to 100%
What does partial agonist have?
- Affinity for receptor
2. Low efficacy
What will partial agonist not produce?
maximum respinse
has efficacy of less than 1
What can partial agonist reduce?
apparent Emax
What are some examples of clinically useful partial agonist?
- Buprenorphine (Subutex)
2. Varenicline (Champix)
What is Buprenorphine?
- Opioid receptor partial agonist
- produces pain relief with lower risk of respiratory depression
- used in situation of drug overdose and/or opioid abuse
What is Varenicline?
- Alpha4/beta 2 selective nicotinic receptor partial agonist
- treat nicotine dependence
What is inverse agonist?
Agent that binds to same receptor as agonist but induces a pharmacological response opposite to that of agonist
What can the effect of inverse agonist be blocked by?
antagonist
What must the receptor of inverse agonist have?
Constitutive activity in absence of ligand
What does inverse agonist do?
Decrease the activity of a receptor below basal level
What is the efficacy of inverse agonist?
<0%
What does inverse agonist do?
- have higher affinity for the active state of receptor
2. shift the equilibrium back to inactive state
What is constitutive activity?
A receptor which is capable of producing a biological response in the absence of bound ligand
What is inverse agonist capable of doing?
Block constitutive activity of a receptor
What is activation of G protein coupled receptors
- Activation of G proteins
- Receptor phosphorylation by GRKS
- B-arrestin migrates to receptor on activation
- leads to receptor internalisation into endosomes
- Internalised receptor/ B arrestin complex forms a scaffold MAP kinases to produce signal in cytosol
- Internalised receptor recycles to cell surface or degraded
What is biased agonism?
Ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand
When is functional selectivity present?
When a receptor has several possible signal transduction pathways
Where is functional selectivity most extensively characterised?
GPCR
What can receptors be seen to do?
Transverse an ‘‘energy landscape’
thermal energy drives the protein into preferred energy wells
What happens when a molecule bind to receptor?
It becomes another thermodynamic species
What are receptor confirmations?
Interconvertible
What is Le Chatelier’s principle?
If a dynamic equilibrium is disturbed by changing the conditions, the position of equilibirum moves to counteract change
What does a ligand enrich?
A particular confirmation that exist in accordance with thermal energy in system and proteins exist in ‘‘ensembles’’ of multiple conformations
What does morphine do?
Activates the mu opioid receptor, a GPCR
What is TRV130?
A G protein-biased ligand
elicits a robust G protein signalling with potency and efficacy similar to morphine
What is TRV130 suggested to be?
Safer and more tolerable therapeutic for treating severe pain
