Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors

• Published in: Pharmacology & therapeutics (Oxford) Vol. 121; no. 2; pp. 160 - 173
• Main Authors: Aloyo, V J, Berg, K A, Spampinato, U, Clarke, W P, Harvey, J A
• Format: Journal Article
• Language: English
• Published: England 01.02.2009
• Subjects: Animals; Drug Delivery Systems; Drug Design; Drug Inverse Agonism; Humans; Receptor, Serotonin, 5-HT2A - metabolism; Receptor, Serotonin, 5-HT2C - metabolism; RNA, Messenger - metabolism; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists - pharmacology; Serotonin Receptor Agonists - pharmacology
• ISSN: 0163-7258
• DOI: 10.1016/j.pharmthera.2008.10.010

Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any ligand. Thus, ligands acting at a constitutively active receptor, can act as agonists, antagonists, and inverse agonists. In vitro studies have also revealed the complexity of ligand/receptor interactions including agonist-directed stimulus trafficking, a finding that has led to multi-active state models of receptor function. Studies with a variety of cell types have established that the serotonin 5-HT(2A) and 5-HT(2C) receptors also demonstrate constitutive activity and inverse agonism. However, until recently, there has been no evidence to suggest that these receptors also demonstrate constitutive activity and hence reveal inverse agonist properties of ligands in vivo. This paper describes our current knowledge of constitutive activity in vitro and then examines the evidence for constitutive activity in vivo. Both the serotonin 5-HT(2A) and 5-HT(2C) receptors are involved in a number of physiological and behavioral functions and are the targets for treatment of schizophrenia, anxiety, weight control, Parkinsonism, and other disorders. The existence of constitutive activity at these receptors in vivo, along with the possibility of inverse agonism, provides new avenues for drug development.