Classification of Agonists and Antagonists



Two examples are presented for illustrating the classification of drugs as agonists and antagonists. The first example examines dopamine without consideration of the various subtypes of dopamine receptors. The second example describes acetylcholine with consideration of its two major receptor subtypes. Follow the available hyperlinks for more detailed descriptions of the various compounds.
 
Types of Agonists & Antagonists (Dopamine)
agonist: a compound that mimics the action of a neurotransmitter direct-acting agonist: binds directly to and activates neurotransmitter receptors   apomorphine
indirect-acting agonist: releases or enhances the action of a neurotransmitter   cocaine
antagonist: a compound that blocks or inhibits the action of a neurotransmitter direct-acting antagonist (aka receptor blocker): binds to the same receptor population as an agonist but fails to activate the target receptors competitive antagonist: competes with an agonist for the same receptor population haloperidol
noncompetitive antagonist: binds irreversibly to the same receptor population as the agonist  
indirect-acting antagonist (term rarely used; rather terms more descriptive of the compound's mode of action are usually used; see examples in the next column) synthesis inhibitor: inhibits the synthesis of a neurotransmitter alpha-methyl-para-tyrosine
storage inhibitor: interferes with the synaptic storage of a neurotransmitter reserpine
Note: Dopamine-receptor subtypes are not considered in the examples given above. 

The second example, using cholinergic systems, takes into consideration the two major cholinergic receptor subtypes.
 

Agonists and Antagonists for Cholinergic Systems
agonist direct-acting agonist   muscarinic receptor subtype (AChRm) muscarine
  nicotinic receptor subtype (AChRn) nicotine
indirect-acting agonist   [nonselective action] neostigmine (reversible inhibitor) 

sarin (irreversible inhibitor)

antagonist direct-acting antagonist competitive antagonist muscarinic receptor subtype (AChRm) atropine
nicotinic receptor subtype (AChRn) mecamylamine (N1 subtype) 

curare (N2 subtype)

noncompetitive antagonist muscarinic receptor subtype (AChRm)  
nicotinic receptor subtype (AChRn)  
indirect-acting antagonist synthesis inhibitor [nonselective action] hemicholinium
release inhibitor [nonselective action] Botulinun toxin

Descriptions of 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).

Naming Conventions & Confusing Nomenclature

Although neostigmine might be called an indirect agonist because it enhances the action of acetylcholine by inhibiting its enzymatic degradation, neostigmine is conventionally called a cholinesterase inhibitor (The more descriptive term is preferred and it's antagonistic effect is inferred from a knowledge of cholinergic activity.). Compounds that interfere with the activity of a neurotransmitter by an action other than binding at the neurotransmitter's target receptors are termed indirect-acting antagonists. (Some authors may also call these compounds noncompetitive antagonists, but this term is best reserved for the special type of antagonists that bind to the neurotransmitter's receptors in a noncompetitive fashion.)

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 a2-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 somewhat preferential action on dopamine autoreceptors (similar to clonidine's effect on 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.)


Copyright 2001 Michael A. Bozarth
E-mail technical problems to: bozarth@buffalo.edu
revised: 29 October 2001 02:53 EST