An agonist is a drug that once bound to the receptor, initiates a change in cellular activity. An example of an agonist action is a drug that binds to the myocardial beta adrenergic receptor and increases the force of contraction. The binding of the agonist often triggers a series of biochemical events which ultimately lead to the alteration in function. The biochemicals which initiate these changes are referred to as second messengers.

Antagonists can bind to receptors but do not initiate a change in cellular function. However, occupation of the receptor can prevent the binding and actions of agonists. Antagonists are also referred to as blockers.

Many chemical substances have the potential to be drugs. Two factors which determine whether a chemical will have drug effects are affinity and some measure of the ability to activate the receptor. This term has been called intrinsic activity, efficacy or intrinsic efficacy.

Affinity is the measure of the tightness with which a drug binds to a receptor.

Intrinsic activity( or another more appropriate term) is the measure of the ability of a drug, once bound to the receptor, to produce a measurable physiologic effect.

Affinity and intrinsic activity are independent properties of drugs. Agonists have both affinity and and the ability to activate the receptor while antagonists have only affinity for the receptor.

The binding of a drug,D, to the receptor, R, can be described by this expression.

where k₁ is the rate of association of the drug with receptor and k_-1 is the rate of DR complex dissociation. At equilibrium the amount of DR formation is equal to the amount of DR dissociation.

Affinity is an important concept in pharmacology. It describes the strength at which a drug binds to the receptor and is equal to the ratio of k₁ and k_-1. It is a property which defines the relative onset and offset of a drug at a receptor. It is unique for each drug in each receptor system and can be used to identify receptors. A high affinity drug has a much greater tendency to bind to the receptor ( a large value for k₁) relative to dissociation from the receptor (a small value for k_-1). Kd is the equilibrium dissociation constant and is the reciprocal of the affinity. This is a term which is widely used to describe the binding of drugs to receptor. The units of the dissociation constant are some measure of concentration such as molar, millimolar, micromolar, or nanomolar. Dissociation constants are small numbers, significantly less than 1, such as 1 x 10^-8M or 10 nanomolar. There is an inverse relationship between the Kd and affinity. The smaller the Kd, the greater the affinity. A drug which has a dissociation constant of 1 nanomolar is said to have higher affinity than a drug which has a dissociation constant of 1 micromolar. This is because 1 nanomolar is much smaller than 1 micromolar.

By appropriate substitution of the equations above we can write:

This points out that when a drug is given at a concentration equal to its dissociation constant, 50% of the receptors will be occupied. The greater the affinity, the less drug will be required to occupy 50% of the receptors because the forward rate constant for receptor association k₁ is larger than the reverse rate constant k-₁. This helps us to understand the extreme potency of some drugs because it takes so little to achieve a large degree of receptor saturation.

To understand the relationship between the occupancy of a receptor by a drug and the measurable physiologic effect, we make the assumption that magnitude of the physiologic response (E)

is proportional to the amount of drug bound to the receptor ([DR]) :

where Emax is the maximum obtainable in the receptor system being studied. We can now write:

This equation states that the effect observed, E/Emax, is determined by the concentration of the drug and its affinity (Kd) for the receptor. In other words, the effect is related to the degree of receptor occupancy. This equation also demonstrates that the higher the affinity a drug possesses for its receptor the less will be required to produce an effect.

Thus far the effect (E) of a drug has only been related to receptor occupancy. However, drugs once bound to a receptor differ in their ability to initiate a change in physiologic activity. This is a more difficult parameter to conceptualize. Drug binding to receptors can be measured quite easily and is governed by relatively straightforward biochemical principles. As will be developed, the ability to activate the receptor and induce an effect encompasses much more than the simple chemical process of drug-receptor binding. Ariens used the the term intrinsic activity, e, as a means to describe the ability of a drug to activate a receptor. We can now write:

Therefore, the ability of a drug to produce a physiologic effect is dependent on receptor occupancy (which is in turn governed by [D] and Kd) and the propensity of the drug to activate the receptor (e). While similar, you should understand that equations #1 and #2 calculate different parameters. Equation #1 determines the degree of receptor occupancy. Equation #2 (with the presence of e) calculates the effect of a drug on a functional response.

While the precise mechanism is not known, agonists have the ability to impart a stimulus to the receptor such that cellular signaling is activated. Agonists differ in their propensity to deliver an activating stimulus to receptors. As a result, agonists can be further divided into full and partial agonists:

Full Agonists: Compounds that are able to elicit a maximal response following receptor occupation and activation.

Partial Agonists: Compounds that can activate receptors but are unable to elicit the maximal response of the receptor system.

Few drugs interact with one and only one receptor. Such a drug would be said to be specific, that is producing effects by specifically interacting with one and only one receptor. Most drugs interact with several receptors and thus have the capability to produce distinctly different pharmacologic effects. The factors that determine which particular effect of a drug will be observed are the affinity and the ability to activate the receptor (intrinsic activity or other term) . These drugs are said to be selective because they can selectively activate one receptor system in preference to another. To illustrate this point consider the following example. A drug is capable of producing actions at 2 distinct receptors. At each of these receptors, the ligand has a different affinity, intrinsic activity, as well as pharmacologic effect.

Receptor System # 1:

K_D = 0.4 nM, intrinsic activity 0.65, effect- lowering of systemic arterial blood pressure.

K_D = 40.0, intrinsic activity 1.0,effect- lethal venticular arrhythmias.

Thus this drug could either be a highly beneficial therapeutic agent or a lethal poison. The effect observed depends on the characteristics of the drug. An overwhelming majority of drugs used in clinical practice produce their therapeutic effects due to their interaction at multiple pharmacologic receptors. This also illustrates that whether the drug will be beneficial or poisonous depends on the skill and knowledge of the individual prescribing the agent. A comprehensive understanding of the principles presented in this lecture is of obvious importance.

Thus far we have made the assumption that the relationship between receptor occupancy [DR]/[RT] and response E/Emax is linear. This linear relationship can be expressed by equation # 2 and is shown in the graph below. In this type of response system, all receptors must be occupied to produce a maximal response. In equation 4, "e" refers to efficacy as defined by Stephensen. This was later modified by Furchgott to relative efficacy "e" = ε [RT]

A= High Receptor Reserve B=Medium Receptor reserve C=No Receptor Reserve

In a non-spare receptor system, the ED₅₀ = Kd. In a spare receptor system, the pharmacologic ED₅₀ and the Kd are not equal. The larger the number of spare receptors, the greater the difference between the ED₅₀ and Kd.

Partial agonists have lower intrinsic activities than full agonists but values greater than competitive antagonists. At certain concentrations partial agonists actually can be antagonists.

To understand how the relationship between occupancy and response can be non linear let us analyze the components which contribute to the response.

G-Protein Coupled Receptors

In a responding system which has a linear relationship between occupancy and physiologic response, there is a direct proportionality between the degree of receptor activation and the generation of second messengers. While this is difficult to conceptualize, it can be thought of as a small amount of receptor occupancy producing a small increase in the level of the second messenger. This small amount of second messenger activates a small increase in physiologic response. In the more realistic nonlinear occupancy versus response system, a small degree of receptor occupancy generates a large increase in second messenger levels which in turn generate an even larger physiologic response. The signal is amplified at every step of the signal transduction process. In this fashion, then, a small degree of receptor occupancy leads to a large physiologic response.

Consider the following example. In a given beta-receptor system, 50,000 cAMP molecules are needed to yield a full response. In a linear response relationship, 50,000 receptors would have to be occupied to give a full response. However, in a nonlinear system, only 100 would be required to achieve a full response.

Continuous exposure of an agonist results in a phenomenon referred to as desensitization. The same concentration of agonist becomes less and less effective at producing the same level of effect. When this desensitization occurs very rapidly, it is referred to as tachyphylaxis. Recent evidence has suggested potential mechanisms by which the process of tachyphylaxis and desensitization occur. The receptor becomes phosphorylated in the third cytoplasmic loop and c-terminal tail. The phosphorylated receptor is less efficient at activating G-protein and also exhibits lower affinity for agonists. The receptors can also be removed from and sequestered away from the cell surface. These events indicate that second messengers not only regulate intracellular processes but are also capable of regulating the receptor systems which generate them.

Traditionally, G-protein coupled receptors were thought to be inactive and that agonist occupation was required to allow the receptor to assume an active conformation. Recently, though, it has been suggested that the receptor can be active without the presence of agonist. The term for this is constitutive activity. Constitutively active receptors are thought to be coupled to second messenger pathways in the absence of agonists.

This has led to the postulate that in addition to traditional agonists, drugs can function as inverse agonists. Inverse agonists bind to constitutively active receptors and shift the equilibrium to the formation of the inactive conformer. In this system an inverse agonist would actually reverse receptor activity. The concept of inverse agonism has added a level of complexity to our thinking of drug action. As the diagram below illustrates, the spectrum of drug activity can range from a full agonist to a full inverse agonist.