From the Guidelines
An inverse agonist is a type of drug that binds to the same receptor as an agonist but produces the opposite pharmacological effect, actively reducing the receptor's baseline activity below its normal level. This occurs because many receptors have some degree of constitutive (spontaneous) activity even without a natural agonist present, as reported in a study on G protein-coupled receptors 1. When an inverse agonist binds to such a receptor, it stabilizes the receptor in an inactive conformation, reducing its signaling below the basal level.
Key Characteristics of Inverse Agonists
- Bind to the same receptor as an agonist
- Produce the opposite pharmacological effect
- Actively reduce the receptor's baseline activity below its normal level
- Common examples include certain benzodiazepine receptor ligands like flumazenil, some antihistamines like diphenhydramine, and beta-blockers like propranolol The clinical significance of inverse agonism versus simple antagonism depends on the specific receptor system and disease state, as discussed in a review of endoscopic sedation 1. For receptors with high constitutive activity, inverse agonists may provide therapeutic advantages over neutral antagonists by more completely suppressing unwanted receptor activity.
Clinical Significance of Inverse Agonism
- Depends on the specific receptor system and disease state
- May provide therapeutic advantages over neutral antagonists for receptors with high constitutive activity
- Can more completely suppress unwanted receptor activity This property explains why some drugs are more effective than others despite targeting the same receptor, as they not only block the effects of natural agonists but also reduce the receptor's inherent signaling capacity.
Examples of Inverse Agonists
- Flumazenil: a benzodiazepine receptor ligand
- Diphenhydramine: an antihistamine
- Propranolol: a beta-blocker It is essential to consider the specific receptor system and disease state when evaluating the potential benefits of inverse agonists, as their effects can vary significantly depending on the context 1.
From the Research
Definition of Inverse Agonist
- An inverse agonist is a type of ligand that binds to a receptor and reduces its constitutive activity, resulting in an opposite effect to that of an agonist 2, 3, 4, 5, 6.
- Inverse agonists can produce a range of effects, including anxiogenic, pro-convulsant, and alerting effects, as seen with beta-carbolines 2.
- They can also have therapeutic significance, such as in the treatment of anxiety-related disorders, congestive heart failure, and psychosis 3.
Characteristics of Inverse Agonists
- Inverse agonists bind to constitutively active receptors, stabilizing them and reducing their activity 3, 5.
- They have negative intrinsic activity, meaning they decrease the receptor's activity below its baseline level 3, 6.
- Inverse agonists can be distinguished from antagonists, which have zero intrinsic activity and simply block the effects of agonists 3, 5.
Examples of Inverse Agonists
- Beta-carbolines, such as ethyl-beta-carbolin, are examples of inverse agonists that act on the benzodiazepine receptor 2.
- Certain antipsychotic drugs, such as clozapine, have inverse agonist activity at the D2 receptor 3.
- Pimavanserin (ACP-103) is a highly selective 5-HT2A inverse agonist that has been shown to attenuate psychosis in patients with Parkinson's disease 3.