Inverse Agonists: An Illustrated Tutorial

Authors: Kiran Panesar, BPharm, MRPharmS, RPh, CPh and Flavio Guzman, MD


Definition

An inverse agonist is a molecule that binds to the same site as an agonist and is considered to be a full agonist. However, it elicits the opposite effect to that of a normal agonist,  i.e.: demonstrates negative efficacy.

Ligand Binding Theory

In a conventional two stage drug receptor interaction (binary) model, receptors can be in either the resting state or the active state. The binding of a ligand to the receptor causes a conformational change in the receptor and may:

  • initiate activity –agonist  with varying degrees of positive intrinsic activity (full or partial)
  • prevent the activity of an agonist – antagonist with zero intrinsic activity.

In the inverse agonist two state model, inverse agonists bind with the constitutively active receptors, stabilize them and shifts receptor equilibrium towards the inactive state, reducing the level of basal activity ie: negative efficacy or negative intrinsic activity.

Here is the integrated view :

As with agonists, the degree of inverse agonism is based upon the affinity of the ligand for the receptor molecule and the effect may be full inverse agonism or partial inverse agonism.

Comparing Inverse Agonists with Partial Agonists and Antagonists

To explain inverse agonists further, lets highlight the differences between:

An inverse agonist vs partial agonist

A partial agonist has a weaker preference than an agonist for the same receptor and shift the equilibrium to a smaller extent than an agonist. Conversely, an inverse agonist has all the properties of a full agonist except that is shifts the equilibrium in the opposite direction to a full agonist.

An inverse agonist vs antagonist

An antagonist reduces the effect of an agonist by preventing it from binding to receptors. Both antagonists and inverse agonists reduce the activity if a receptor and, in the presence of an agonist, reduce its activity. However, unlike inverse agonists, antagonists do not have any effect in the absence of an agonist.

Common Inverse Agonists

As the definition of inverse agonists became clearer, more and more molecules that exhibit inverse agonism with clinical applications have been established. Inverse agonism was first discovered when B-carbolines and other compounds that were shown not only to have an antagonistic effect at benzodiazepine receptors but also to elicit an effect that was the opposite of the benzodiazepine in the absence of benzodiazepines. Currently there are a number of well established true inverse agonists including antipsychotics, antidepressants and other psychopharmacological drugs that have inverse agonist activity at serotonin, dopamine, histamine, opioid, cannabinoid and muscarinic receptors.

Histamine Receptors

The histaminergic receptors, H1, H2, and H3 all exhibit constitutional activity. H1 receptor antagonists such as cetirizine and loratadine reduce this constitutive receptor activity and behave as inverse agonists by stabilizing the inactive conformation of the H1 receptor.  H2 antagonists such as cimetidine, ranitine, famotidine reduce basal cAMP levels and behave as inverse agonists.

Beta-blockers

The beta-blockers carvedilol and bucindolol demonstrate a lower level of inverse agonism than propranolol and nadolol. The beneficial effects of carvedilol in congestive failure can therefore be explained by inverse agonism as can be the beneficial effects of clozapine in the management of psychosis and candesartan prescribed for patients with cardiac hypertrophy.

GABA receptors

The benzodiazepine-GABA receptor complex is a pentameric structure comprised of the α, β and, ƴ subunits in different proportions. Various agents including general anesthetics, benzodiazepines, barbiturates, hypnotics and anti-epileptics act as inverse agonists or antagonists. Inverse agonists acting on the BDZ receptors may have a full or partial inverse agonistic effect. Recently discovered molecules that behave as inverse agonists at BDZ-GABA receptors have been shown to antagonize the effects of ethanol in locomotor behavior and suppress ethanol intake in selectively bred alcohol preferring rates.

Opioid Receptors

Naloxone acts as an inverse agonist at the µ receptors in morphine pre-treated tissues, where it stimulates the cAMP levels but inhibits GTPƴS binding. This effect is however not noted in untreated tissues.

Serotonin Receptors

5-HT receptors play a role in psychosis, learning and memory. Thus inverse agonism activity of drugs at these receptors may be the basis of the antipsychotic effects of these drugs. Drugs that display such activity include chlorpromazine, risperidone, mirtazapine and mianserine.

Contrary to conventional thought, not all drugs acting at dopamine receptors are antagonists. Several compounds such as haloperidol and clozapine are in fact inverse agonists.

Miscellaneous Drugs

Other drugs that have inverse agonist activity are listed in the table below:

Receptor target Examples
α-adrenoceptor Prazosin, terazosin
B-adrenoceptor Metoprolol, carvedilol, bisoprolol
M1 muscarinic Pirenzipine
M3 muscarinic Darifenacin, tolterodine
Angiotensin AT1 Candesartan, irbesartan
Oxytocin OT Atosiban
Cysteinyl leukotriene Montelukast, zafirlukast
Cannabinoid Rimonabant

 

References

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