PHSC1613 Pharmacology - Lecture 2 Ligand-Receptor Theory: Ligand Binding vs Effect

Equilibrium dissociation constant (Kd)

derived from the relationship: kon[L][R]=koff[LR], it is a measure of the affinity that a ligand has for binding to a receptor

Ligand affinity for receptor

Kd is a measure of what?

LR formation rate constant

What is kon?

LR dissociation rate constant

What is koff?

Rate

At equilibrium, is the concentration or the rate equal?

Fraction or concentration of receptors bound by ligand

What does B represent?

Bmax

represents the maximum possible concentration of receptors bound by ligand, which is determined by the total concentration of receptors

Total concentration of receptors

What determines the Bmax or maximum possible concentration of bound receptors?

Ligand concentration at half Bmax

How can Kd be found on a binding curve?

Fractional occupancy

the fraction of receptors occupied by ligand at any ligand concentration

Receptor occupancy

another name for fractional occupancy

Kd of a ligand-receptor interaction

determines what fraction (B/Bmax) of total receptors will be occupied at a given free concentration of ligand [L], regardless of total receptor concentration

Ligand concentration at 0.5

How can Kd be found on a binding curve where the y-axis is in fractions?

Receptor or fractional occupancy and drug response or effect

increase with concentration giving them similar hyperbolic curves

Emax and EC50

While a binding curve uses Bmax and Kd, what would a response curve use?

Ligand concentration at half Emax

How can EC50 be found on a response curve?

E

represents the effect observed at concentration [L]

Emax

the maximal effect that can be produced by the ligand

EC50

the concentration of ligand that produces 50% of the maximal effect

Binding drives effect

Why would binding and effect curves look similar?

Threshold, slope, and maximal asymptote

three parameters and properties of dose-response curves that quantitate the activity of the drug

Logarithm

For curve plotting, sometimes the __________ of the drug concentration is used to form a sigmoidal curve instead of a hyperbolic curve to make it easier to read.

Hyperbolic

curve of drug response against drug concentration on a linear axis

Sigmoidal

curve of drug response against drug concentration on a logarithmic axis

X

Which axis is the logarithmic value used for dose-response curves?

Low

At what concentrations for a dose-response curve is the effect changing rapidly?

High

At what concentrations for a dose-response curve is the effect changing slowly?

Threshold

concentration at which you see a response

Maximal asymptote

refers to the plateau where a drug's effect, binding, or reaction rate reaches its peak, saturating all receptors/enzymes

More effect with little concentration change

If a dose-response curve has a steeper slope, what does that mean?

Affinity

reflects the tendency of a drug to combine with a receptor

Tendency of drug to combine with receptor

What does affinity reflect?

Low Kd

What Kd would a high-affinity drug have?

Bind a greater fraction of receptors

What would a high-affinity drug do compared to a low-affinity drug?

Low affinity

If a drug has a high Kd, does it have a high or low affinity?

Efficacy

reflects the maximal response a drug can produce

Maximal response a drug can produce

What does efficacy reflect?

High Emax

What Emax would a high-efficacy drug have?

Elicit a greater maximum response

What would a high-efficacy drug do compared to a low-efficacy drug?

Low efficacy

If a drug has a low Emax, does it have a high or low efficacy?

Potency

a measure of the drug concentration that's required to produce a given response

Drug concentration required to produce a given response

What does potency measure?

Low EC50

What EC50 would a high-potency drug have?

Less drug to achieve response

What would a high-potency drug require compared to a low-potency drug?

Low potency

If a drug has a high EC50, does it have a high or low potency?

Affinity and efficacy

make up drug potency

Efficacy and potency

two ways of quantifying agonism

Agonism

Efficacy and potency are two ways of quantifying what?

Antagonist

a drug that binds to a receptor and exhibits zero efficacy

Relative efficiency of occupancy-response coupling

determined by both the receptor itself, and also by the "downstream" biochemical events that transduce receptor occupancy into cellular response

Simple

relationship between drug occupancy and response where the response produced is directly proportional to the number of bound receptors

Complex

relationship between drug occupancy and response where the response produced is not necessarily directly proportional to the number of receptors bound

Ligand gated ion channels

example of a simple relationship between drug occupancy and response (because ion current produced by drug is directly proportional to number of ion channel receptors bound)

Response may reach max before full receptor occupancy or max response may be limited by downstream mediators

Two possible explanations for a complex drug occupancy and response relationship

Spare receptors

phenomenon where, for a given pharmacologic response, it is possible to elicit a maximum biologic response at a concentration of agonist that does not result in occupancy of all of the available receptors

Receptor reserve

another name for spare receptors

Nonlinear

Are "receptor reserve" and "spare receptors used to describe linear or nonlinear kinetics?

Maximum response without all receptors bound by agonist

What can be achieved in a system with spare receptors?

Nothing

If there are spare receptors, activating additional receptors will do what for the response?

Kd = EC50

How do Kd and EC50 compare in a scenario where there are an equal number of receptors and effects (thus, no spare receptors)

Kd > EC50

How do Kd and EC50 compare in a scenario where there are spare receptors and not as many effectors and receptors?

Maximum response can be achieved without all receptors occupied by an agonist

If a system has spare receptors, what does that mean for the response?

EC50 will be smaller than Kd

If a system has spare receptors, what does that mean for the EC50 and Kd?