3. Agonists Flashcards
(61 cards)
1
Q
Define ‘agonist’
A
a ligand (neurotransmitter, hormone, drug) that combines with receptors to elicit a cellular response
2
Q
General steps from an agonist to effect
A
- receptor
- agonist-receptor complex
- action
- effect
3
Q
Steps of salbutamol to effect
A
- B2-adrenoreceptor
- salbutamol-b2 adrenoreceptor complex
- increased cAMP
- bronchodilation
4
Q
Why is dose important?
A
- all things are poison in the wrong dose as wouldn’t have effect if they didnt have poisonous qualities
5
Q
Correct dose of aspirin
A
300-600 mg
6
Q
Two types of dose-response curve?
A
- concentration plotted against effect
- semi-logarithmic plot of agonist concentration against percentage response
7
Q
Shapes seen on dose-response curve
A
- if not log its a half semi circle
- if log used, its sigmoidal
8
Q
Difference between dose and concentration given
A
- dose is the initial given
- concentration is the amount in the systemic circulation
9
Q
2 types of dose-response relationships
A
- graded
- quantal
10
Q
Explain graded dose-response relationships
A
- response of a particular system
- in isolated tissue, animal or patient
- measured against agonist concentration
11
Q
Explain quantal dose-response relationships
A
- drug doses (agonist or antagonist)
- required to produce a specified response determined in each member of a population
12
Q
How does a log axis work?
A
- 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
13
Q
Why is a log used?
A
to make a concise graph
14
Q
Why do we plot dose-response graphs?
A
- allows estimation of Emax
- and of dose required for 50% of Emax/EC50
- allows determination of efficacy and potency
15
Q
Define ‘Emax’
A
maximal response with highest concentration in system
16
Q
Define ‘EC50’
A
concentration/dose required to produce 50% of maximal response
17
Q
Define ‘potency’
A
- the amount of drug needed to produce an effect
- how well a drug binds, the signalling involved and effect recieved at the end
18
Q
Define ‘affinity’
A
strength with which an agonist/drug binds to a receptor
19
Q
Explain the two state hypothesis
A
- 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
20
Q
What does R and R* mean?
A
- rested
- activated
21
Q
Affinity is the ratio of …
A
how easy an agonist (drug or natural product) sticks vs comes off
22
Q
Receptor saturation is easily/tough to measure/d but …
A
- easily (with max number of binding sites Bmax)
- difficult to get a measure of how avidly the drug binds (affinity/Kd)
23
Q
How to find amount of specific binding sites?
A
total sites - non-specific
24
Q
How to work out affinity?
A
- use k1/k-1
- k1 being the rate of association of agonist with receptor
- k-1 being rate of AR complex dissociation
25
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)
26
Kd is what?
the equilibrium dissociation constant
27
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)
28
What does Kd tell us?
- can be used to identify unknown receptor
- used to quantitatively compare affinity of diff drugs on same receptor
29
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)
30
How to show inverse relationship between affinity and Kd?
affinity is k1/k-1
Kd is k-1/k1
31
The lower the Kd, the greater the ...
affinity
32
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
33
True affinity can only be determined by ...
binding dose relationships
34
Potency depends on what 4 things?
- affinity
- efficacy
- receptor density
- efficiency of stimulus-response mechanisms used
35
Define 'potency'
the amount of drug needed to produce given effect
- found at EC50
36
The lower the EC50, the greater the ...
potency
37
Agonists with high potency tend to have ...
high affinity
38
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
39
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
40
When an agonist binds to a receptor, this induces what?
a conformational change that sets off a chain of biochemical events called 'an action'
41
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
42
A full agonist has ... efficacy and a partial agonist has ... efficacy
high
low
43
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
44
In a partial agonist with low efficacy, ... is less likely. Explain
AR*
- unable to produce a maximum response even when occupying all available receptors
45
In a full agonist, the maximum response produced corresponds to ...
maximum response a tissue can give
46
Define 'partial agonist'
- a ligand that combines receptors to elicit maximum response
- which falls short of maximal response the system is capable of producing
47
List 3 partial agonists
- varenicline
- tamoxifen
- aripiprazole
48
Role of varenicline
- nicotine receptor partial agonist
- for smoking cessation
49
Role of tamoxifen
- estrogen receptor partial agonist
- for use in estrogen dependent breast cancer
50
Role of aripiprazole
- antipsychotic
- partial agonists at selected dopamine receptors
51
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
52
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
53
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
54
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
55
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
56
Example of an inverse agonist
- Beta-carbolines on GABAa receptors
- anxiogenic rather than anxiolytic
57
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
58
Explain positive allosteric modulators
- not active alone but increase affinity and/or efficacy of endogenouds agonists
- e.g diazepam, propofal, isoflurane
59
Explain negative allosteric modulators
- not active alone but decrease affinity and /or efficacy of endogenous agonists
- e.g mGluR5 dipraglurant
60
Define 'desensitisation of receptors'
effect of drug reduces continual/repeated administration
- called tachyphylaxis
61
Contributing factors to densentisisation of receptors
- conformational changes in receptor
- internalisation of receptors
- depletion of mediators
- altered drug metabolism
- other physiological/homeostatic responses
