Unit 4 - Receptor pharmacology Flashcards
What is an antagonist?
Bind to the receptor in such a way that they produce a different induced fit and do NOT activate receptor
- block natural messenger so cannot bind and activate
What is an agonist?
Bind to the receptor binding site in a similar way to the natural messenger and activates receptor
What is selectivity?
Relative affinity
- ligand has higher affinity for one receptor over another
Ligand will preferentially bind to one receptor more avidly than another
- at a lower concentration
What effect does better selectivity have?
Fewer side effects
Give examples of selective and non selective drugs
Atenolol - selective B1-adrenoceptor antagonist
Propranolol - non-selective B1-adrenoceptor antagonist
What effect does a drug with a low affinity have?
Need to have a higher concentration of drug to produce a response
How can selectivity be observed?
Response profiles - not used any more Concentration response curves Radioligand binding - direct method of measuring affinity of ant/agonist for a receptor
How are most receptors distributed?
Most receptors are not ubiquitously distributed
- distributed in discrete tissues/organs in the body
How is assaying selectivity carried out?
Different tissues can express different populations of receptor types
How do non-selective drugs affect tissues?
Non-selective drugs affect all tissues
How do selective drugs affect tissues?
Selective drugs affect some tissues but not all tissues
- response in SOME tissues
What type of adrenoceptor subtypes are found in the heart?
Beta 1
Beta 2
What effect does adrenaline have on beta 1 and beta 2 adrenoceptors in the heart?
Adrenaline is non-selective
- will affect both types of receptor
- heart rate increases
- coronary flow increases
- vasodilation
What effect does dobutamine have on beta 1 and beta 2 adrenoceptors in the heart?
Dobutamine is selective for Beta 1 adrenoceptor
- heart rate increases
- no effect on coronary flow
What effect does salbutamol have on beta 1 and beta 2 adrenoceptors in the heart?
Salbutamol is selective for Beta 2 adrenoceptor
- no effect on heart rate
- coronary flow increases
- vasodilation
How can selectivity be revealed in tissue containing different receptor subtypes?
Concentration response curves
- non-selective agonist
- affinity for receptor is pretty much the same
- sees entire receptor population as the same so targets equally
- selective agonist
- multiple curves
- 2 stacked on top of each other
- 2 EC50 values
- 2 affinity types
What is the function of radioligand binding?
Determines binding affinity of ligand for binding site
Affinity is a constant for a ligand-binding site
- receptor
- EXCEPTION
- different affinity states due to G-protein binding
Efficacy is NOT a factor
- no distinction between agonists and antagonists
What are the two types of radioligand binding?
Saturation
Competition binding
What is saturation binding?
Add radioligand to sample of tissue
- drug labelled with radioactivity
Wash unbound drug away
Measure the amount of radioactivity from sample
What is specific binding?
Only interested in binding to the receptor
- specific
Describe specific binding
Saturable
- finite number of receptors to bind to
- upper limit
- the number of receptors present
- plataeu when all the receptors are full
Describe non-specific binding
Non-saturable
- will always increase with increasing addition of ligand
What can be worked out from saturation binding?
Dissociation constant, KD - affinity constant, KA - 1/KD Maximum specific binding - total number of receptors present
What is competition binding?(radioligand)
Add one concentration of radioligand
Displace radioligand from receptors with unlabelled ligand
- increasing concentration of unlabelled ligand
Radioligand and ‘cold’ ligand can be the same
- simplifies things
- but often use known radioligand with known affinity for receptor
Affinity is calculated based on the relative affinities and concentration of radioligand
- known concentration and affinity of radioligand
Why does the radioactivity in competition binding never go to zero?
Non specific not bound to receptor so can’t be displaced
How did scientists know there were 2 histamine receptors?
In 1948, histamine antagonists already clinically used
- to treat ulcers
- H1 receptor selective
Histamine caused gastric acid secretion
- insensitive to available antihistamines
- suggested presence of a second type of histamine receptor
Clinical utility for treatment of peptic ulcers
