3. Agonists Flashcards
Define ‘agonist’
a ligand (neurotransmitter, hormone, drug) that combines with receptors to elicit a cellular response
General steps from an agonist to effect
- receptor
- agonist-receptor complex
- action
- effect
Steps of salbutamol to effect
- B2-adrenoreceptor
- salbutamol-b2 adrenoreceptor complex
- increased cAMP
- bronchodilation
Why is dose important?
- all things are poison in the wrong dose as wouldn’t have effect if they didnt have poisonous qualities
Correct dose of aspirin
300-600 mg
Two types of dose-response curve?
- concentration plotted against effect
- semi-logarithmic plot of agonist concentration against percentage response
Shapes seen on dose-response curve
- if not log its a half semi circle
- if log used, its sigmoidal
Difference between dose and concentration given
- dose is the initial given
- concentration is the amount in the systemic circulation
2 types of dose-response relationships
- graded
- quantal
Explain graded dose-response relationships
- response of a particular system
- in isolated tissue, animal or patient
- measured against agonist concentration
Explain quantal dose-response relationships
- drug doses (agonist or antagonist)
- required to produce a specified response determined in each member of a population
How does a log axis work?
- each unit increase represents an exponential increase on previous value
- base 10 logs are used for dose-response
- 10 fold increase from one unit to the next (1 to 10 to 100
Why is a log used?
to make a concise graph
Why do we plot dose-response graphs?
- allows estimation of Emax
- and of dose required for 50% of Emax/EC50
- allows determination of efficacy and potency
Define ‘Emax’
maximal response with highest concentration in system
Define ‘EC50’
concentration/dose required to produce 50% of maximal response
Define ‘potency’
- the amount of drug needed to produce an effect
- how well a drug binds, the signalling involved and effect recieved at the end
Define ‘affinity’
strength with which an agonist/drug binds to a receptor
Explain the two state hypothesis
- when receptor is resting, when not occupied by agonist (drug or natural product) any basal activity is low
- forms a complex when occupied and equilibrium state shifts - more likely here for receptor to be activated, more receptive to turning on signalling system
- shows how likely it is that the receptor is active or inactive
What does R and R* mean?
- rested
- activated
Affinity is the ratio of …
how easy an agonist (drug or natural product) sticks vs comes off
Receptor saturation is easily/tough to measure/d but …
- easily (with max number of binding sites Bmax)
- difficult to get a measure of how avidly the drug binds (affinity/Kd)
How to find amount of specific binding sites?
total sites - non-specific
How to work out affinity?
- use k1/k-1
- k1 being the rate of association of agonist with receptor
- k-1 being rate of AR complex dissociation
A high affinity drug means what?
- much greater tendency to bind to receptor (much larger k1)
- relative to dissociation from receptor (smaller k-1 value)
Kd is what?
the equilibrium dissociation constant
Define ‘Kd’
- a physiochemical constant
- the same for any given receptor and drug combo in tissue in any species (as long as receptor is the same)
What does Kd tell us?
- can be used to identify unknown receptor
- used to quantitatively compare affinity of diff drugs on same receptor
If we assume a direct relationship between receptor occupancy and response, what can we assume?
concentration of ligand at which 50% of the available receptors are occupied is Kd
- inverse relationship between Kd and affinity
- a lower Kd indicates a tighter ligand-receptor interaction (higher affinity)
How to show inverse relationship between affinity and Kd?
affinity is k1/k-1
Kd is k-1/k1
The lower the Kd, the greater the …
affinity
Can you work out affinity from the dose-response relationship?
- no
- don’t know how many of the receptors are occupied
- need to see % of receptors occupied
True affinity can only be determined by …
binding dose relationships
Potency depends on what 4 things?
- affinity
- efficacy
- receptor density
- efficiency of stimulus-response mechanisms used
Define ‘potency’
the amount of drug needed to produce given effect
- found at EC50
The lower the EC50, the greater the …
potency
Agonists with high potency tend to have …
high affinity
If there is a linear relationship between receptor occupation and biological effect, then what?
Kd and EC50 are equal
- meaning 50% receptro occupation means 50% effect
Explain spare receptors/receptor reserves
- if linear relationship between receptor occupation and biological effect, EC50 and Kd are equal
- but many receptors can amplify signal duration and intensity
- so only a fraction of total receptors for a specific ligand have to be occupied to elicit maximum response from cell
- these systems are said to have spare receptors
When an agonist binds to a receptor, this induces what?
a conformational change that sets off a chain of biochemical events called ‘an action’
Define ‘efficacy’
- the ability of an agonist to activate a receptor i.e evoke an action at cellular level
- determined by receptor-effector system
- refers to maximum effect an agonist can produce regardless of dose
A full agonist has … efficacy and a partial agonist has … efficacy
high
low
In a full agonist with high efficacy, … is very likely.
Explain
- AR*
- produce a maximum response while occupying only a small % of receptors available
- may only occupy 1 or 2 in CNS
In a partial agonist with low efficacy, … is less likely. Explain
AR*
- unable to produce a maximum response even when occupying all available receptors
In a full agonist, the maximum response produced corresponds to …
maximum response a tissue can give
Define ‘partial agonist’
- a ligand that combines receptors to elicit maximum response
- which falls short of maximal response the system is capable of producing
List 3 partial agonists
- varenicline
- tamoxifen
- aripiprazole
Role of varenicline
- nicotine receptor partial agonist
- for smoking cessation
Role of tamoxifen
- estrogen receptor partial agonist
- for use in estrogen dependent breast cancer
Role of aripiprazole
- antipsychotic
- partial agonists at selected dopamine receptors
Why are partial agonists good sometimes?
- encourage endogenous reactions but reduced response
- don’t inhibit natural response
- can lower chances of breast cancer for example without completely stopping estrogen production
What’s the new data showing a link between partial and full agonists?
- suggests receptor operated ion channels like nAChR and GlyR
- channels can open and close equally as well in response to either PA or FA
What evidence is noted that shows two state model is maybe too simple?
- shows receptor can only work in AR and AR*
- new evidence suggests receptors can activate in absence of ligands i.e R* or change state depending on GPCR function
- ternary complex model (four active states
Explain inverse agonists
- have higher affinity for AR state than AR*
- shown in many classical competitive antagonists like cimetidine for H2 and atropine (M)
- around 85% of competitive antagonists are actually inverse agonists
Why are inverse agonists not antagonists?
- binds to low level activity receptor and turns down the activity
- doesn’t block it so not an antagonist
Example of an inverse agonist
- Beta-carbolines on GABAa receptors
- anxiogenic rather than anxiolytic
How do benzodiazepines act as allosteric modulators?
- act on GABAa receptors
- drug has own unique binding sites, they bind together so can’t block GABA binding site
- increases Ka for GABA
- increases efficacy of GABA
- increases chloride ions that come through channel
Explain positive allosteric modulators
- not active alone but increase affinity and/or efficacy of endogenouds agonists
- e.g diazepam, propofal, isoflurane
Explain negative allosteric modulators
- not active alone but decrease affinity and /or efficacy of endogenous agonists
- e.g mGluR5 dipraglurant
Define ‘desensitisation of receptors’
effect of drug reduces continual/repeated administration
- called tachyphylaxis
Contributing factors to densentisisation of receptors
- conformational changes in receptor
- internalisation of receptors
- depletion of mediators
- altered drug metabolism
- other physiological/homeostatic responses
