Examples of Inverse Agonists
Inverse agonists are compounds that bind to constitutively active receptors and reduce their basal activity, producing effects opposite to those of agonists. 1, 2
Mechanism of Action
- Inverse agonists stabilize the inactive conformation (R) of receptors according to the two-state receptor model, shifting the equilibrium away from the active conformation (R*) 3
- Unlike neutral antagonists (which have equal affinity for both active and inactive conformations), inverse agonists preferentially bind to and stabilize the inactive receptor state 2, 4
- This results in negative intrinsic activity, reducing the spontaneous or constitutive activity of receptors 1
Examples of Inverse Agonists by Receptor Type
Cannabinoid (CB) Receptor Inverse Agonists
- Rimonabant is a well-documented CB1 receptor inverse agonist that was developed for obesity treatment 5, 1
- CB2 receptor inverse agonists have shown potential as antitussive agents in preclinical studies 6
- Hemopressin is a peptide ligand that acts as both an antagonist and inverse agonist at cannabinoid receptors, demonstrating antinociceptive properties 1
Benzodiazepine Receptor Inverse Agonists
- Several compounds act as inverse agonists at the benzodiazepine binding site of GABA-A receptors 1, 3
- These agents produce effects opposite to those of benzodiazepine agonists (anxiety, increased vigilance, convulsions) 3
- Development of anxioselective benzodiazepine inverse agonists without habit-forming potential is underway 1
Other Notable Inverse Agonists
- β-blockers: Many conventional β-blockers (propranolol, nadolol) exhibit inverse agonist activity, while others (carvedilol, bucindolol) show lower levels of inverse agonism 1
- Antihistamines: Nearly all H1 and H2 antihistamines conventionally classified as antagonists have been shown to be inverse agonists 1
- Antipsychotics: Many D2 receptor antagonists used as antipsychotics demonstrate significant inverse agonist activity 1
- Opioid antagonists: Naloxone and other opioid antagonists can function as inverse agonists, which may explain naloxone-induced withdrawal syndrome in opioid dependence 1
- Serotonergic agents: Pimavanserin (ACP-103), a selective 5-HT2A inverse agonist, has been developed for psychosis in Parkinson's disease without extrapyramidal side effects 1
Clinical Significance
- Inverse agonism may explain therapeutic benefits of certain drugs in conditions like congestive heart failure (carvedilol), psychosis (clozapine), and cardiac hypertrophy (candesartan) 1
- Sustained treatment with inverse agonists can produce greater upregulation of receptor levels than neutral antagonists, which has therapeutic implications 7
- Inverse agonists may have therapeutic potential in diseases associated with constitutively active mutant receptors or wild-type receptor overexpression 3
Experimental Approaches to Identify Inverse Agonists
- Methods to detect inverse agonists include determining ligand affinity at R and R* with binding experiments 3
- Measuring modulation of G protein activity (GTP binding and hydrolysis) or effector activity can also identify inverse agonist properties 3
- Using constitutively active mutant receptors can exaggerate inverse agonist effects, facilitating their identification 7
Inverse agonism represents an important aspect of drug-receptor interaction with significant therapeutic potential that extends beyond traditional receptor antagonism 1, 2.