Responses to Agonists Flashcards
Explain agonist-receptor binding using the law of mass action
Reaction between drug and receptor is governed by
the Law of Mass Action
= Rate of a reaction is proportional to the molecular
concentration of the reactants
In the case of agonist-receptor binding, the law of mass action is expressed as follows:
[A] + [R] <–> [AR] (agonist/drug + free reactant = agonist reactant complex)
At equilibrium: forward rate = back rate
forward reaction rate : k+1
backward reaction rate : k-1
Equilibrium constant = KA = k-1/k+1 = KD (a measure of the affinity between the agonist and the receptor)
KD + affinity
Factors influencing affinuty
K D is a measure of affinity; measured as a
concentration (M)
Affinity - a measure of how tightly a drug binds to a
receptor
- higher affinity of a drug for a receptor => lower value of
KD
K D = k +1/k -1 (small top/big bottom = fast forward reaction) - Measures conc. of drug that occupies 50% of binding sites
at equilibrium
using reaction : KD = [drug][receptor]/[complex]
KD is especially dependent on 2 factors:-
* electronic/hydrophobic match of drug to receptor
* (bonding and conformation)
* steric match of drug to receptor
* (conformation and size)
Hill-Langmuir Equation
drug conc: xA
receptor conc : Ntot - Na
complex conc : Na
proportional occupancy (pA )
p A = Na/Ntot [proportion of receptors bound i.e. in complex over the total receptors]
pA = xA / xA + KD
Hill-langmuir equation : relates receptor occupancy
to drug concentration (xA) :
Explain the relationship between receptor occupancy and drug
concentration
the relationship between drug concentration ([Drug]) and receptor occupancy is directly proportional
higher drug concentrations result in a greater fraction of receptors being occupied by the drug (pA)
*pA = Na / Ntot (conc of complex/ conc of total no. of receptors)
A lower Kd implies that a smaller concentration of free drug is needed to achieve a given level of receptor occupancy.
Higher affinity results in a more effective binding at lower drug concentrations.
Explain the relationship between drug occupancy and response to explain how potency is measured
The relationship between drug concentration and pharmacological response is often represented by a dose-response curve.
As the drug concentration increases, the receptor occupancy increases, leading to a corresponding increase in response.
–> Potency is a measure of the amount or concentration of a drug required to produce a specific effect.
=> It is often quantified by the effective concentration at which 50% of the maximal response is achieved (EC50).
Mathematically, potency is related to the drug concentration and the dose-response curve
E.G. a lower EC50 = higher potency.
Agonist dose-response curve features and compare/contrast
X-Axis (Dose or Concentration of drug)
Y-axis represents the dependent variable = observed pharmacological response or effect elicited by the drug.
A steep dose-response curve
1) High steepness :
* high receptor occupancy = = a relatively small change in dose or concentration leads to a significant change in the observed response
* Higher potency = the drug is effective and produces response even at lower concentrations.
2) EC50 (Effective Concentration 50):
concentration of the agonist at which 50% of the maximal response is achieved = a measure of the potency of the agonist.
* Lower EC50 values = higher potency i.e. agonist is effective at lower concentrations.
3) Efficacy (Maximal Response):
the maximum effect or response produced by the agonist = intrinsic efficacy of the agonist.
* A higher plateau suggests higher intrinsic efficacy.
4) Full Agonist vs. Partial Agonist:
or agonist = 1
* for partial agonist >0 and <1
A full agonist produces the maximal response achievable for a particular receptor system.
A partial agonist, even at maximal concentration, cannot elicit the same level of response as a full agonist.
Describe the Hill coefficient and what it measures
a crucial parameter in the Hill-Langmuir Equation
Hill Coefficient n>1: suggests positive cooperativity. Positive cooperativity means that as one drug molecule binds to the receptor, it increases the likelihood of other drug molecules binding to nearby sites. This results in a steeper dose-response curve.
n=1: no cooperativity, and each binding event is independent. The curve is sigmoidal but not as steep as when positive cooperativity is present.
n<1: negative cooperativity. Negative cooperativity means that the binding of one drug molecule makes it less likely for other drug molecules to bind to nearby sites. This results in a less steep dose-response curve.
Explain why a drug’s potency may not necessarily be the same
concentration as its affinity.
- Efficacy Differences:
Potency is primarily a measure of the concentration needed to produce a given effect, potency is about the concentration needed to achieve an effect, while efficacy is about the maximum effect a drug can achieve. Drugs with different affinities can have similar potencies but different efficacies due to the strength and nature of their interactions with receptors. - Receptor Reserve:
In some cases, a biological system may have more receptors than necessary to produce a maximal response. A drug with lower affinity may still occupy a sufficient number of receptors to elicit a full response, making its potency comparable to a higher-affinity drug. - Partial Agonism:
If a drug is a partial agonist, it may have lower efficacy even at high occupancy of receptors. In such cases, a drug with lower affinity but higher intrinsic efficacy may produce a more potent response than a drug with higher affinity but lower intrinsic efficacy.
Binding Assay
a laboratory technique used to measure the binding affinity between a molecule (such as a drug or ligand) and its target, typically a receptor or protein
–> Measures OCCUPANCY and AFFINITY; gives information on:
* Maximal number of binding sites (Bmax)
* Affinity (KD ) (concentration at which 50% of receptors
are occupied at equilibrium)
(go to half of Bmax and find concentration of drug. Low conc of drug = low Kd = high affinity)
a rectangular hyperbola shape
why can’t we use functional assays (Bioassay) to measure affinity
e.g. concentration response curve
x axis : log drug concentration
Measures RESPONSE
* gives information on:
o Maximal response (Emax)
o Intrinsic efficacy and potency
o Potency (EC50) (concentration at which 50% of maximal
response is elicited), Kmax,
= CANNOT be used to measure affinity…WHY?
* Higher potency = the drug is effective and produces response even at lower concentrations.
* Lower EC50 values = higher potency i.e. agonist is effective at lower concentrations.
* A higher plateau suggests higher intrinsic efficacy.
–> a sigmoidal curve
pD2
pD2 is a measure of the potency of an agonist.
pD2 = -log(EC50)
A lower EC50 value indicates a more potent agonist == A higher pD2 value indicates a more potent agonist, as it corresponds to a lower EC50 value.
