TY - JOUR
T1 - Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors
AU - Aloyo, V. J.
AU - Berg, K. A.
AU - Spampinato, U.
AU - Clarke, W. P.
AU - Harvey, J. A.
N1 - Funding Information:
The authors wish to acknowledge support provided by the National Institutes of Health (USPHS grants GM58652 and MH16841-40), the National Alliance for Research on Schizophrenia and Depression and the Institut National de la Santé e de la Recherche Médicale (INSERM)-Bordeaux 2 University.
PY - 2009/2
Y1 - 2009/2
N2 - 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-HT2A and 5-HT2C 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-HT2A and 5-HT2C 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.
AB - 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-HT2A and 5-HT2C 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-HT2A and 5-HT2C 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.
KW - Constitutive activity
KW - Inverse agonism
KW - Serotonin 5-HT receptor
KW - Stimulus trafficking
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U2 - 10.1016/j.pharmthera.2008.10.010
DO - 10.1016/j.pharmthera.2008.10.010
M3 - Review article
C2 - 19109993
AN - SCOPUS:59949102887
SN - 0163-7258
VL - 121
SP - 160
EP - 173
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
IS - 2
ER -