Inverse agonism

Inverse agonism

In pharmacology, an inverse agonist is an agent which binds to the same receptor binding-site as an agonist for that receptor and reverses constitutive activity of receptors (i.e. The basal activity that is there without binding of a ligand). Inverse agonists exert the opposite pharmacological effect of a receptor agonist.

Receptor agonists, competitive antagonists and inverse agonists bind to the same receptor types. The pharmacological effect of an inverse agonist is measured as the negative value of the agonist primarily due to the historical findings of the already known agonist. Therefore, if the agonist has a positive value and the inverse agonist has a negative

value, the antagonist for the receptor takes both the agonist and inverse agonist back to a neutral state.

The graphic below shows an example of the receptor response of a ligand-gated ion channel (e.g. GABA).

When no ligand is bound, the receptor displays constitutive activity: the ion channel is slightly opened causing a small chloride ion influx.Addition of a full agonist evokes a change in conformation, which leads to further opening of the ion channel resulting in further hyperpolarisation.Binding of an inverse agonist reverses the constitutive activity and leads to a complete closure of the ion channel. The result is a depolarisation.