DRUG BINDING TO RECEPTOR

How does the drug bind to the receptor, in terms of saturation properties?

Specific binding: if you have 10 receptors in a test tube, you cannot bind more than 10 molecules. This is the idea of receptor saturation

How do we know what binds to specific receptors?

We can figure this experimentally by making a homogenate of (for example) rat muscle in a test tube and measuring how much of the targeted receptor is there.

-When the muscle is homogenized, you get a mixture of vesicles with receptors in your test tube.

-Next you radioactively label the drugs that you want to bind to the receptors, and mix them with the homogenate. Then separate the radioactive materials out and measure the amount that is bound.

-BUT, what you measure includes both specific interactions (with receptors) and non-specific interactions (within vesicles) because you have radioactively labeled drugs that are attached to receptors along with those that are free-floating within the vesicles. The specific measurement will increase to the point of saturation and then level off [look at figure 2-4], because there are only a finite amount of receptors available. The non-specific measurement is continuously increasing and does not become saturated; it is equally as concentrated with the solution extracellularly because there are no specific receptors within the vesicles, only trapped radioactive drugs.

-Thus, you need a control mechanism to properly measure specific vs. non-specific interactions. So if we can kill all the receptors and make them unable to bind to the radioactive drug, then our results will include only those radioactive drugs within the vesicles (those that do not bind the receptor). We then take this amount and subtract it from our original experiment without the control, to find the specific amount of drug interactions with receptors. This tells us specific binding.

Specific binding is very important to know because it tells us 2 things:

1. how much receptor is there

2. how strong the receptor binding is, because it tells us the concentration that

must be present for the specific binding to occur.

Why do we care about specific binding?!?

Because if we have two drugs and are measuring the specific binding, they may be different… The receptor number may be the same but the affinity is different, so the drug’s effects will depend on the drug’s ability to remain bound to the receptor. If one drug remains bound longer than the other, even though there are the same number of receptors available for each drug, the two drugs will need to have different dosages to maintain effectiveness because the one with less binding affinity will dissociate more quickly.

Summarizing…

Drugs reach receptors with binding sites. There are two important parameters:

1. Saturation: amount of molecules bound to the receptors

2. Affinity: an expression of how much the receptor likes the drug; more affinity means that the drug can be given at a lower dose. So, the affinity is the ratio between the time that the molecule binds to a protein and the time it takes to dissociate.

Category: Pharmacology Notes