Medical Pharmacology Topics   

Receptor Binding

An agonist is a chemical that, when bound to a receptor, stimulates the receptor to produce its appropiate biological response (D). The response may be stimulation or inhibition, depending on the type of receptor.

                k1
R + L    RL     D
                k-1

The velocity of the forward and reverse reactions are proportional to the concentration of ligand andreceptor, and the concentration of ligand-receptor complex, respectively:

vforward  =  k1 [R] [L]     and     vreverse  =  k-1 [RL]

This relationship illustrates the probability that ligand and receptor will form a complex within a set time interval. If we assume that (1) interactions are fully reversible, (2) total receptor (RT) available is a much smaller number than ligand concentration, and (3) the system approximates equilibrium (d[RL]/dt » 0), a hyperbolic equatuion can be derived:

[RL]  =  [R]T [L]
             Kd + [L]

Kd is the dissociation constant, equal to k-1/k1. The higher the affinity of ligand for a receptor, the lower the Kd. The value of Kd equals the ligand concentrration producing half maximal binding.

In a similar fashion, most drugs directed towards enzymes are inhibitors and can be understood using the Michaelis-Menten equation:

v  =   _vmax [S]_
          Km + [S]

Competitive inhibitors preclude binding of substrate, although excess substrate can overcome the competition.

            S
    E ES E + P
C
   EC

The apparent Km is increased but vmax remains the same:

v  =   _____vmax [S]_____
          Km(1+[C]/KC) + [S]

Noncompetitive inhibitors bind to enzyme independet of substrate, and cannot be overcome by excess substrate. They may bind to the enzyme reversibly or irreversibly.

S     E ES E + P N           N    EN            ESN

OR

S     E ES E + P N    EN

Noncompetitive inhibitors may or may not affect Km, but always lower vmax.

v  =   {vmax /(1+[N]/KN)} [S]
                   Km + [S]

A semilogaritmic plot of ligand binding yields a sigmoidal dose-response curve symetrical around Kd. This curve allows to compare the action of different agonists for the same receptor. <insert graph>

An antagonist is a chemical that blocks the effect of an agonist on a receptor. A competitive antagonist can be overcomed by excess agonist. A noncompetitive antagonist cannot be overcomed by excess agonist and may be reversivble or irreversible. An irreversible antagonist forms a chemical bond with the receptor or chemically inactivates it.

In another kind of dose-response curve, a quanta dose response curve, the y-axis repersents the prportion of a populatin that respond to a drug in an all-or-none fashion (ex. awake/sleep, dead/alive). These curves are used to express drug safety information.

It is customary to obtain the effective dose and letal dose for a percentage of the population (ex. ED50 is the effective dose for 50% of the population, LD50 is the letal dose). The therapeutic index (TI) is the ratio of LD5 and ED95, and is an indication of the selectivity of the drug to produce a therapeutic effect versus a toxic effect. The terms therapeutic window or safety margin are often used and refer to a range of dosses over which a therapeutic effect can be produced without serious toxic effects.

Selectivity is the ability of a drug to produce a given therapeutic effect at doses that do not produce toxic or other unwanted effects. Selectivity, not potency, is the key to safer and more clinically useful drugs. In other words, the separation between the quantal curves for effects and side effects is more important than the actual location of the curve.

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