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

@article{Smith2006RisperidoneIB,
  title={Risperidone Irreversibly Binds to and Inactivates the h5-HT7 Serotonin Receptor},
  author={Carol Smith and Tariq Rahman and Nicole Toohey and Joseph E. Mazurkiewicz and Katharine Herrick-Davis and Milt Teitler},
  journal={Molecular Pharmacology},
  year={2006},
  volume={70},
  pages={1264 - 1270}
}
Risperidone displays a novel mechanism of antagonism of the h5-HT7 receptor. Pretreatment of the cells with 5 or 20 nM risperidone, followed by removal of the drug from the media, renders the 5-HT7 receptors unresponsive to 10 μM 5-HT for at least 24 h. Thus, risperidone seems to be producing a rapid, long-lasting inactivation of the h5-HT7 receptor. Whole-cell radioligand binding studies indicate that risperidone interacts in an irreversible or pseudo-irreversible manner with the h5-HT7… 

Figures from this paper

Clozapine and other competitive antagonists reactivate risperidone-inactivated h5-HT7 receptors: radioligand binding and functional evidence for GPCR homodimer protomer interactions
TLDR
The ability of the non-inactivating drugs to bind h5-HT7 orthosteric sites and reverse the wash-resistant effects of risperidone or 9-OH-risperidones, also bound to h5,HT7 Orthosteric Sites, is evidence for protomer–protomer interactions between h5 -HT7 homodimers.
Human 5-HT7 Receptor-Induced Inactivation of Forskolin-Stimulated Adenylate Cyclase by Risperidone, 9-OH-Risperidone and Other “Inactivating Antagonists”
TLDR
It is reported that brief exposure of the h5-HT7 receptor-expressing cells to inactivating drugs, followed by removal of the drugs, results in potent and efficacious irreversible inhibition of forskolin-stimulated adenylate cyclase activity.
Pharmacological Analysis of the Novel, Rapid, and Potent Inactivation of the Human 5-Hydroxytryptamine7 Receptor by Risperidone, 9-OH-Risperidone, and Other Inactivating Antagonists
TLDR
The results indicate that ris peridone and 9-OH risperidone may be producing 5-HT7 receptor inactivation by different mechanisms than lisuride, bromocryptine, metergoline, and methiothepin.
Risperidone-Induced Inactivation and Clozapine-Induced Reactivation of Rat Cortical Astrocyte 5-Hydroxytryptamine7 Receptors: Evidence for In Situ G Protein-Coupled Receptor Homodimer Protomer Cross-Talk
TLDR
Evidence suggests that a native (nonmutated) GPCR, in its native membrane environment (cortical astrocyte primary culture), can function as a homodimer with protomer-protomer cross-talk, an intrinsic property of 5-HT7 receptors in vitro and ex vivo.
Pharmacological analysis of the novel, rapid and potent inactivation of the human 5-HT7 receptor by risperidone, 9-OH-risperidone and other “inactivating antagonists”
TLDR
The results indicate that ris peridone and 9-OH risperidone may be producing 5-HT7 receptor inactivation by different mechanisms than lisuride, bromocryptine, metergoline, and methiothepin.
Cellular mechanisms of the 5-HT7 receptor-mediated signaling
TLDR
The 5-HT7 receptor is coupled to the stimulatory Gs-protein, and receptor stimulation results in activation of adenylyl cyclase (AC) leading to a rise of cAMP concentration, andThis review focuses on molecular mechanisms responsible for the 5- HT7 receptor-mediated signaling.
Current Limitations and Candidate Potential of 5-HT7 Receptor Antagonism in Psychiatric Pharmacotherapy
TLDR
To explore candidate novel applications for the treatment of several neuropsychiatric disorders, including mood disorders, schizophrenia, and other cognitive disturbance disorders, the effects of 5-HT7R antagonism on transmission and intracellular signaling systems are discussed.
Synthesis and in vitro evaluation of oxindole derivatives as potential radioligands for 5-HT(7) receptor imaging with PET.
TLDR
Known 5-HT(7) selective phenylpiperazinyl-butyloxindole derivatives are modified so that they may be labeled either with carbon-11 or fluorine-18, and two compounds display a promising in vitro profile with respect to PET imaging of the 5- HT( 7) receptor in thalamic regions.
Long-Acting κ Opioid Antagonists Disrupt Receptor Signaling And Produce Noncompetitive Effects By Activating C-Jun N-Terminal Kinase*
TLDR
Results suggest that the long duration KOR antagonists disrupt KOR signaling by activating JNK, and both norBNI and JDTic were found to stimulate c-Jun N-terminal kinase (JNK) phosphorylation in HEK293 cells expressing KOR-GFP but not in untransfected cells.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 25 REFERENCES
Biochemical profile of risperidone, a new antipsychotic.
TLDR
Risperidone enhanced at nanomolar concentrations the stimulated [3H]norepinephrine efflux from cortical slices and it similarly reversed the inhibition by clonidine, at concentrations corresponding to its binding affinity for alpha-2 adrenergic receptors.
Persistent Binding and Functional Antagonism by Xanomeline at the Muscarinic M5 Receptor
TLDR
Results clearly indicate that wash-resistant binding of xanomeline to the muscarinic M5 receptor is accompanied by persistent antagonism of receptor function and suggest a relationship between the efficacy of xnomeline and the functional consequences of its wash- resistant binding at different Muscarinic receptor subtypes.
Stable expression of constitutively activated mutant h5HT6 and h5HT7 serotonin receptors: inverse agonist activity of antipsychotic drugs
TLDR
The inverse agonist mechanism-of-action of the atypical antipsychotic drugs at the h5HT7 receptors may be different from the typical antipsychotics drugs as these drugs displayed far higher potencies as inverse agonists at the H5 HT7 receptor.
Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors.
TLDR
The authors examined the affinities of 36 typical and atypical antipsychotic agents for the cloned rat 5-hydroxytryptamine-6 and rat5-HT7 receptors in transiently expressed COS-7 cells or stably transfected HEK-293 cells to identify those with high affinity for the newly discovered 5-HT6 receptor.
Constitutive Activity of Brain Serotonin Receptors: Inverse Agonist Activity of Antipsychotic Drugs
TLDR
These studies demonstrate the procedures for producing and characterizing constitutively active forms of serotonin receptors, including the demonstration of inverse agonist activity of drugs on these receptors.
Constitutive activity of G-protein coupled receptors: emphasis on serotonin receptors.
TLDR
Significant alterations in the classical model of ligand-receptor interactions are suggested, and the possibility of developing drugs that lower the level of constitutive activity for pharmacologists and medicinal chemists is considered.
Desensitization of G protein-coupled receptors and neuronal functions.
TLDR
An important and specific role of GRKs and beta arrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia.
Historical review: a brief history and personal retrospective of seven-transmembrane receptors.
  • R. Lefkowitz
  • Biology, Chemistry
    Trends in pharmacological sciences
  • 2004
Agonist high and low affinity state ratios predict drug intrinsic activity and a revised Ternary complex mechanism at serotonin 5‐HT2A and 5‐HT2C receptors
TLDR
Data produced support a revised model for the molecular events coupling GPCR to activation of G‐proteins and indicate that a strong correlation between the KL/KH ratio and intrinsic activity for agonist action at G PCR is consistent with the existence of R*.
Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values.
The pKi values of 13 reference typical and 7 reference atypical antipsychotic drugs (APDs) for rat striatal dopamine D-1 and D-2 receptor binding sites and cortical serotonin (5-HT2) receptor binding
...
1
2
3
...