Agonist & Antagonist Actions

Agonist & Antagonist Actions

This section gives more detailed descriptions of the compounds listed in the above tables.

Agonists

An agonist is a ligand that binds to a receptor and produces a biological effect (direct acting) or a compound that indirectly produces the same effect of a neurotransmitter (indirect acting). These compounds usually mimic the actions of a neurotransmitter. Their neurophysiological effect and their effect on behavior can be either stimulatory or inhibitory, depending on the function of the neurotransmitter they mimic. For examples, cholinergic systems are usually neurophysiologically excitatory and a cholinergic agonist (e.g., nicotine) stimulates behavior (e.g., increases locomotor activity). Dopaminergic systems are often neurophysiologically inhibitory, but dopamine activation (e.g., amphetamine) usually stimulates behavior (probably through disinhibition). GABAergic neurons are inhibitory, so GABA agonists usually inhibit neural activity and behavior.

Antagonists

An antagonist is a ligand that binds to a receptor but does not produce a biological effect (direct acting) or a compound that indirectly inhibits the effect of a neurotransmitter (indirect acting). These compounds usually block or inhibit the actions of a neurotransmitter. For examples, cholinergic systems are usually stimulatory and cholinergic antagonists can inhibit behavior. On the other hand, GABAergic systems are inhibitory, so GABA antagonists usually stimulate behavior.

Direct-Acting Agonist

These compounds bind directly to and activate neurotransmitter receptors. Their action does not reply on endogenous neurotransmitter activity. For example, if the neurotransmitter is depleted through synthesis inhibition, a direct-acting agonist will still produce the effect normally associated with a given neurotransmitter. However, because their action depends on binding at neurotransmitter receptors, direct-acting (e.g., competitive) antagonists can block their effects. And because direct-acting agonists bind to specific receptors, they can be selective for various receptor subtypes.

Indirect-Acting Agonist

These compounds release or enhance the action of an endogenous neurotransmitter. Their action depends on the integrity of the neurotransmitter system they stimulate. For example, a synthesis inhibitor will block the effect of an indirect-acting agonist as will a competitive antagonist. And because indirect-acting agonists act through endogenous neurotransmitters, they are not selective for various receptor subtypes.

Directing Acting Antagonist

These compounds are ligands that bind to the same receptor as the neurotransmitter but do not "activate" the receptor. They are ligands with little or no efficacy (i.e., intrinsic activity). Competitive antagonists 'compete' with the neurotransmitter (or other ligand) for binding at the receptor site. Increases in agonist concentration can reverse the effects of a competitive antagonist (i.e., the agonist dose-response curve is shifted to the right).

Agonists with Antagonistic Actions

It's possible for an agonist to have an antagonistic action. The compound would still be called an agonist, but an agonist with antagonistic actions. This case is perhaps best illustrated considering the action of clonidine.

Clonidine is an agonist, an alpha-2 agonist to be precise. But it acts primarily on noradrenergic autoreceptors thereby decreasing norepinephrine release. Thus clonidine is a direct-acting noradrenergic agonist with indirect-acting antagonist action at other noradrenergic targets. (It has the physiological/behavioral effect of an antagonist at most doses, but it's still technically an agonist!) Carlson confuses his classification of clonidine by classifying it as an agonist on one table and as an antagonist on another -- it is an agonist with antagonistic actions.

Apomorphine is a dopaminergic agonist. At very low doses, apomorphine has a son noradrenergic autoreceptors) and decreases dopamine release (behaviorally, it produces sedation). But at most doses apomorphine's postsynaptic action on dopamine receptors dominates, so it produces behavioral stimulation similar to amphetamine and cocaine. (Yes, dopamine release goes down after apomorphine, but apomorphine's direct stimulation of postsynaptic dopamine receptors renders dopamine release redundant.)

Receptor: Any cellular macromolecule that a drug binds to initiate its effects.

Drug: A chemical substance that interacts with a biological system to produce a physiologic effect.

All drugs are chemicals but not all chemicals are drugs. The ability to bind to a receptor is mediated by the chemical structure of the drug that allows it to interact with complementary surfaces on the receptor. Drugs that interact with receptors can be classified as being either agonists or antagonists. Once bound to the receptor an agonist activates or enhances cellular activity. Examples of agonist action are drugs that bind to beta receptors in the heart and increase the force of myocardial contraction or drugs that bind to alpha receptors on blood vessels to increase blood pressure. The binding of the agonist often triggers a series of biochemical events that ultimately leads to the alteration in function. The biochemicals that initiate these changes are referred to as second messengers. Antagonists have the ability to bind to the receptor but do not initiate a change in cellular function. Because they occupy the receptor, they can prevent the binding and the action of agonists. Hence the term antagonist. Antagonists are also referred to as blockers.

Factors Governing Drug Action

Two factors that determine the effect of a drug on physiologic processes are affinity and intrinsic activity.

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

Intrinsicactivity is a measure of the ability of a drug once bound to the receptor to generate an effect activating stimulus and producing a change in cellular activity.

Affinity and intrinsic activity are independent properties of drugs. Agonists have both affinity, that is, the ability to bind to the receptor, as well as intrinsic activity, the ability to produce a measurable effect. Antagonists, on the other hand, only have affinity for the receptor. This property allows antagonists to bind to the receptor. However, because antagonists do not have intrinsic activity at the receptor no effect is produced. Because they are bound to the receptor, they can prevent binding of agonists. This is a diagram of a G-protein coupled receptor. Notice how the amino acids that make up the receptor protein can contribute functional groups to allow a drug to bind to this receptor.

The binding of a drug to a receptor is determined by the following forces:

Hydrogen bonds
Ionic bonds
Van der Waals forces
Covalent bonds

Understanding Affinity

To bind to a receptor the functional group on a drug must interact with complementary surfaces on the receptor. The binding of a drug, illustrated here as D, to the receptor, illustrated as R, can be described by this expression.

By appropriate substitution of the equations above we can write:

This equation describes the binding of drugs to receptors and states that the amount of drug bound to the receptor is dependent on the drug concentration and Kd.
Question: WHAT percentage of the total receptor population will be 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.
Understanding the Consequences of Receptor Occupancy

It is apparent that for a drug to produce an effect it must first bind to a receptor. To understand the relationship between receptor occupancy and the generation of 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 maximal obtainable effect when all receptors are occupied. 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 helps us to understand the extreme potency of some drugs. A drug with very high affinity will achieve a large degree of receptor saturation at very low concentrations.

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 receptor conformation and 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. The ability to activate the receptor and induce an effect encompasses much more than the simple chemical process of drug-receptor binding. Let us use the symbol, e to define intrinsic activity. Intrinsic activity describes the ability of a drug induce changes in receptor structure leading to alterations in cellular activity. 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. #1

Full and Partial Agonists

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.

Drugs which are full agonists are arbitrarily assigned an intrinsic activity value of 1. Partial agonists, which cannot produce the same maximal effect as full agonists will have intrinsic activity values less than 1. The effect of partial and full agonists on equation # 2 is apparent. Because partial agonists have e values less than 1, the value of E/Emax will be some fraction of the value obtained with a full agonist.

Dose-Response Curves

Dose-response relationships are a common way to portray data in both basic and clinical science. For example, a clinical study may examine the effect of increasing amounts of an analgesic on pain threshold. To present the data, the concentration of the drug would be plotted on the x-axis and the effect on pain threshold would be presented on the y-axis. A plot of drug concentration ([D]) versus effect (E/Emax) (or for that matter DR/RT) is a rectangular hyperbola. Notice how the drug effect reaches a plateau or maximum. This is because there are a finite number of receptors. Hence, the response must eventually reach a maximum. However, the hyperbolic plot is a cumbersome graph because drug concentrations often vary over 100 to 1000-fold. This necessitates a long X-axis. To overcome this problem, the log of the drug concentration is plotted versus the effect. A plot of the log of [D] versus E/Emax is a sigmoid curve.

As illustrated below, the position and shape of the log-dose response curve is dependent on the affinity of the ligand for the receptor and its intrinsic activity. Affinity determines the position of the dose-response curve on the X-axis, while intrinsic activity affects the magnitude of the response.

/ Norepinephrine and phenylephrine are full agonists with intrinsic activity values of 1. However, Norepinephrine has a higher affinity for the receptor. As is illustrated, affinity affects the position of the dose-response curve on the x-axis.
/ Clonidine and Methoxamine are partial agonists. Clonidine has a higher affinity but a lower intrinsic activity than does Methoxamine. Intrinsic activity affects the magnitude of the response.

Spare Receptors

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 most physiological systems in which drugs will be administered, the relationship between receptor occupancy and response is not linear but some unknown function f of receptor occupancy. In the graph, this unknown function is presented as being hyperbolic. As the graph depicts in this type of system, all receptors do not have to be occupied to produce a full response. Because of this hyperbolic relationship between occupancy and response, maximal responses are elicited at less than maximal receptor occupancy. A certain number of receptors are "spare." Spare receptors are receptors which exist in excess of those required to produce a full effect. There is nothing different about spare receptors. They are not hidden or in any way different from other receptors.

Assume an agonist with a KD = 50 nM and an e=1.

In a linear occupancy response system / In a non linear occupancy-response system with f= 1.5 and f=2
Occupancy / Response
10 nM = 16
20 nM = 28
40 nM = 44
50 nM = 50
100 nM = 66
200 nM = 80 / 16
28
44
50
66
80
/ Occupancy / Response f=1.5 / Response f=2.0
10 nM = 16
20 nM = 28
40 nM = 44
50 nM = 50
100 nM = 66
200 nM = 80 / 25
42
66
75
99
100 / 32
56
88
100
100
100
/ A= High Receptor Reserve
B=Medium Receptor reserve
C=No Receptor Reserve

Antagonists

Antagonists exhibit affinity for the receptor but do not have intrinsic activity at the receptor. An antagonist that binds to the receptor in a reversible mass-action manner is referred to as a competitive antagonist. Because the antagonist does not have intrinsic activity, once it binds to the receptor, it blocks binding of agonists to the receptor. A key point about competitive antagonists is that like agonists, they bind in a reversible manner. This has important implications regarding the effect competitive antagonists have on the configuration of the dose-response curve of agonists. Because competitive antagonists bind in a reversible manner, agonists, if given in high concentrations, can displace the antagonist from the receptor and the agonist can then produce its effect. The antagonist action can, in effect, be surmounted. Because the antagonist can be completely displaced, the agonist is still able to produce the same maximal effect observed prior to antagonist treatment. However, because higher agonist concentrations were necessary to displace the antagonist, the agonist dose-response curve is shifted to the right in the presence of a competitive antagonist. This can be illustrated with two equilibrium equations:

The antagonist [B] and agonist [D] are competing for the same limited number of receptors [R]. The drug that binds to the receptor in the highest concentration will be determined by two factors.

These factors are the affinities of the agonist and antagonist for the receptor and their relative concentrations. In the presence of a competitive antagonist equation #2 is modified as follows:

Where [B] is the concentration of antagonist and Kb is the affinity exhibited by the antagonist for the receptor. Inspection of this equation will reveal that the affinity of the agonist, Kd, is modified by the term (1+[B]/Kb). If the concentration of antagonist [B] is large in relation to its affinity Kb, the term (1+[B]/Kb) will be large. Therefore, the major effect of an antagonist is to shift the dose-response curve for an agonist to the right. The dose-response curve obtained in the presence of a competitive antagonist is parallel to the dose-response curve obtained in the absence of antagonist. If the Kb is small and the concentration high, the antagonist will have a more pronounced effect than if the Kb is large and the antagonist concentration is small. This also points out that large concentrations of the agonist can overcome the actions of a competitive antagonist. Assume that the agonist, D, and the antagonist, B, have equal affinity for the receptor. If the concentration of D is much larger than B, the value of E/Emax will not be significantly decreased by the presence of the antagonist. This again illustrates that the actions of the competitive antagonist can be surmounted by the agonist.

/ Prazosin is a competitive antagonist of the action of agonist PE

To summarize, the key features of a competitive antagonist are:

Reversible binding to the receptor.
The blockade can be overcome by increasing the agonist concentration.
The maximal response of the agonist is not decreased.
The agonist dose-response curve in the presence of a competitive antagonist is displaced to the right parallel to the curve in the absence of agonist.

Irreversible Receptor Antagonists

Another type of antagonist is referred to as an irreversible receptor antagonist. The properties of irreversible antagonists are markedly different from competitive antagonists. Irreversible receptor antagonists are chemically reactive compounds. These ligands first bind to the receptor. Following this binding step, the ligand then reacts with the functional groups of the receptor. The consequence of this chemical reaction is that the ligand becomes covalently bound to the receptor. Because a chemical bond is formed, an irreversible ligand does not freely dissociate from the receptor. It remains attached to the receptor for a long period of time. The synthesis of new receptor protein may be required to generate a receptor free of an irreversible blocker. Because the ligand is covalently bound to the receptor, the binding of agonists, and hence their pharmacologic activity, are blocked. Unlike competitive antagonists, the blocking activity of irreversible receptor antagonists can not be overcome by increasing the agonist concentration. The antagonism therefore cannot be overcome by increasing the agonist concentration. Recall, that the effect of an agonist is proportional to the active drug-receptor complexes formed. Because an irreversible receptor antagonist reduces the total number of active receptors, [RT], the maximal pharmacologic effect Emax is also decreased. The reduction in maximal agonist reponse is the hallmark of irreversible antagonists. The shape of the dose-response curve is also altered because of this decrease in maximal effect. The dose-response is shifted to the right and the maximal response is depressed.

To summarize, the properties of irreversible receptor blockers are:

Chemically reactive compound, therefore covalently binds with the receptor
The receptor is irreversibly inactivated and the blockade can not be overcome with increasing agonist concentration..
Shifts the agonist dose-response curve to the right and depresses maximal responsiveness.

Applications to Therapeutics

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 a single receptor. Most drugs interact with several receptors and thus have the capability to produce distinctly different pharmacologic effects. Some of these effects could be beneficial, some could be toxic. Such a drug would be said to be a selective. The factors that determine which particular effect of a drug will be observed are the affinity and intrinsic activity of a drug .