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Agonists And Antagonists Notes

Pharmacology Notes > Drug Development (BIOL10822) Notes

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Drugs: From Molecules to Man - Lecture 6 (16/02/2018)

Agonists and Antagonists

Pharmacologists are interested in the binding as well as the function of molecules.

Measuring binding does not tell us anything about what a drug does. Clearly, the effect of a drug is more important, and pharmacologists often measure functional parameters instead of occupancy parameters.

Something that activates a receptor is called an Agonist.

Similarly to measuring the binding, plotting a functional response will also give you a sigmoidal curve if you use a log scale.

However different terms are used to describe this curve, as instead of Bmax, Emax is used, and instead of Kd we talk about
EC50.

The EC50 is the concentration at which 50% of the maximum effect is reached.

Therefore the equation of this curve looks very much like the occupancy equation.

E=

Emax ×[ D]
E C 50+[ D]




E = Effect.
Emax = Maximum Effect.
D = Concentration of Drug.
EC50 = Concentration giving 50% max effect.

There are other forms of this equation too. For whole organisms, when a drug is administered it is befeficial to know the best Dosage to give. Therefore the EC50 is replaced with ED50 (The dose giving 50% of maximal effect).

To summarize, the shape of concentration effect curves will usually follow a "Hill-Langmuir"
like relationship - a rectangular hyperbola on a linear scale and sigmoidal on a log scale.

We can use a very similar equation to the Hill Langmuir equation to describe such relationships but it is important to realise that we are not dealing with occupancy, only the effects. Functional Assays

The functionality is not always related to the occupancy.

Here is a simpler example to explain why Kd and EC50 are often different. Suppose we have a GPCR system in which one receptor can activate 4 enzyme molecules.

Further, imagine that the cell has 6 receptors and 12 enzymes. We can get all of the enzymes activated and see a maximum response by activating only half of the receptors. In other words we have spare receptors. This phenomenon will cause the EC50 to be much lower than the Kd. This is quite common.

We can also get situations where a receptor can shift into a high affinity but non-active state upon prolonged exposure to agonists. In such cases the Kd will be much lower than the
EC50.

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