Risperidone Irreversibly Binds to and Inactivates the h5-HT₇ Serotonin Receptor

Abstract

Risperidone displays a novel mechanism of antagonism of the h5-HT 7 receptor. Pretreatment of the cells with 5 or 20 nM risperidone, followed by removal of the drug from the media, renders the 5-HT 7 receptors unresponsive to 10 M 5-HT for at least 24 h. Thus, risperidone seems to be producing a rapid, long-lasting inactivation of the h5-HT 7 receptor. Whole-cell radioligand binding studies indicate that risperidone interacts in an irreversible or pseudo-irreversible manner with the h5-HT 7 receptor, thus producing the inactivation. Internalization of the h5-HT 7 receptor was not detected by monitoring green fluorescent protein-labeled fluorescent forms of the h5-HT 7 receptor exposed to 20 nM risperidone. Ten other antagonists were tested for h5-HT 7 -inactivating properties, and only 9-OH-risperidone and methiothepin were found to demonstrate the same anomalous properties as risperidone. These results indicate that the h5-HT 7 receptor may possess unique structural features that allow certain drugs to induce a conformation resulting in an irreversible interaction in the intact membrane environment. This may indicate that the h5-HT 7 receptor is part of a subfamily of G-protein-coupled receptors (GPCRs) possessing this property or that many GPCRs have the potential to be irreversibly blocked, but only select drugs can induce this effect. At the very least, the possibility that highly prescribed drugs, such as risperidone, are irreversibly antagonizing GPCR function in vivo is noteworthy.

Synthesis and In Vitro Evaluation of Oxindole Derivatives as Potential Radioligands for 5-HT7 Receptor Imaging with PET

“…4 Other atypical antipsychotics also have relatively high affinity for the 5-HT 7 receptor, but their involvement in alleviating depressive symptoms through blocking the 5-HT 7 receptor remains to be investigated. 5,6 In vivo studies of cerebral 5-HT 7 receptor binding in humans would thus provide a significant advance in the understanding of the above-mentioned physiology and pathophysiology. Positron emission tomography (PET) is used to quantify neuroreceptor binding in vivo, and the availability of an appropriate PET radiotracer for the 5-HT 7 receptor would be of particular interest.…”

Human 5-HT7 Receptor-Induced Inactivation of Forskolin-Stimulated Adenylate Cyclase by Risperidone, 9-OH-Risperidone and Other “Inactivating Antagonists”

“…It is one of a group of drugs believed to initiate their effects through interactions with the D 2 dopamine and 5-HT 2A serotonin receptors (Meltzer et al, 1989;Roth et al, 1994). These interactions have been shown to be classic competitive antagonist interactions (Roth et al, 1994;Smith et al, 2006). In previous publications, using h5-HT 7 receptor-expressing HEK293 cells, we reported the rapid, potent inactivation of h5-HT 7 receptor stimulation of cAMP production by six antagonists: risperidone, 9-OH-risperidone, methiothepin, bromocriptine, metergoline, and lisuride (Smith et al, 2006;Knight et al, 2009).…”

The Serotonin-7 Receptor as a Novel Therapeutic Target

“…[10][11][12][13][14][15][16][17] In particular, several of the compounds listed in Table 1 are effective antidepressants, and in animal models, the antidepressant efficacy of aripiprazole is reversed in animals lacking 5-HT 7 receptors, 8 and the serotonin release and antidepressant actions of selective serotonin reuptake inhibitors (SSRIs) are enhanced by selective 5-HT 7 antagonists. 3,5,8 Three novel agents characterized as antipsychotics have 5-HT 7 antagonist properties among their most potent pharmacologic actions ( Figure 1), 2,10,13,14 and 1 of these, lurasidone, in late-stage clinical development as an antipsychotic, is actually "5-HT 7 preferring, " with 5-HT 7 antagonism its most potent property.…”

“…1,2 Now comes the 5-HT 7 receptor onto the scene, 2-17 not just because of the development of specific compounds allowing characterization of this receptor, 3,5,[7][8][9] but also because of the discovery that several of the known antidepressants and antipsychotics block 5-HT 7 receptors, and that this 5-HT 7 antagonism may account in part for the therapeutic properties of these drugs, especially antidepressant actions. [10][11][12][13][14][15][16][17] Localization and Function of 5-HT 7 Receptors Serotonin-7 receptors are postsynaptic G protein-linked receptors that may regulate serotonin-glutamate interactions. 3,4,7 They are distributed in areas that explain their functions, namely, the suprachiasmatic nucleus of the hypothalamus; the hippocampus, cortex, and thalamus; and also in the midbrain raphe nuclei, probably on GABA interneurons or on glutamate terminals.…”