Agonist and dose-response curves Flashcards
What is an agonist?
A ligand that combines with receptors to elicit a cellular response.
What dose of aspirin is required to relieve a headache?
300-600mg
What is a graded dose-response relationship?
Response of a particular system (isolated tissue), measured against agonist concentration
What is a quantal dose-response relationship?
Drug doses (agonist or antagonist), required to produce a specific response determined in each member of the population.
What does affinity describe?
The strength with which an agonist/drug binds with a receptor
What does Emax allow?
Efficiency to be determined
What does EC50 allow?
Potency to be determined
What is Bmax?
Maximum number of binding sites
What is K1?
The rate of association of the agonist with the receptor
What is K-1?
The rate of AR complex dissociation
What does affinity equal?
K1 / K-1
What is Kd?
Equilibrium dissociation constant
Measures affinity
What does high affinity mean?
A much greater tendency to bind to the receptor (large K1) relative to its dissociation from the receptor (small K-1)
What does Kd equal?
K-1 / K1
How is true affinity determined?
By binding-dose relationships
What is potency?
Elicit a response by binding to a critical number of receptors at low concentration (high affinity) compared with other drugs acting on the same system with lower affinity.
What does potency depend on?
Affinity of drug
Efficacy of drug
Receptor density
The efficiency of stimulus-response mechanisms used.
The lower the EC50 value…
The greater the potency
When are Kd and EC50 equal?
The linear relationship between receptor occupation and biological effect
Spare receptors:
Many receptors can amplify signal duration and intensity.
Only a fraction of total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell
What does efficacy describe?
The ability of an agonist to activate a receptor. (EG to evoke an ‘action’ at the cellular level)
What is efficacy?
When an agonist binds to a receptor, this includes a conformational change that sets off a chain of biochemical events (an ‘action’)
Full agonist (high efficacy)
Produces a maximum response while occupying only a small percentage of receptors available.
Partial agonist (low efficacy)
Unable to produce a maximum response even when occupying all the available receptors
Examples of partial agonists
Varenicline
Tamoxifen
Aripiprazole
Varenicline
Nicotine receptor partial agonist for smoking cessation
Tamoxifen
Estrogen receptor partial agonists for use in estrogen-dependent breast cancer
Aripiprazole
Antipsychotic, partial agonists at selected dopamine receptors
Inverse agonists
Have a higher affinity in AR state than AR* state.
Many classical competitive antagonists display inverse agonist activity.
~85% of competitive antagonists are actually inverse agonists.
Examples of inverse agonists
Cimetidine (H2)
Pirenzepine (M2)
Atropine (M)
Positive allosteric modulators (PAM)
Not active alone but increase affinity and/or efficacy of endogenous agonist
Examples of Positive allosteric modulators (PAM)
Diazepam
Propofol
Isoflurane
Negative allosteric modulators (NAM)
Not active alone but decrease affinity and/or efficacy of endogenous agonists.
Examples of Negative allosteric modulators (NAM)
mGluR5 dipraglurant
Desensitization of receptors
The effect of the drug reduces with continual/repeated administration. (Termed tachyphylaxis)
