Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo.
Reads0
Chats0
TLDR
Of the selective 5-HT2A antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-ht2A receptors and potentiated PCP-hyperlocomotion; the other 5- HT2A receptor antagonists were without effect.Abstract:
Dysregulation of the 5-HT(2A) receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT(2A) receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT(2A) down-regulation to their efficacy is not known. We hypothesized that down-regulation of cortical 5-HT(2A) receptors contributes to the therapeutic action of atypical antipsychotic drugs. To test this hypothesis, we assessed the effect of chronically administered antipsychotics (clozapine, olanzapine, and haloperidol) and several 5-HT(2A) antagonists [ketanserin, altanserin, α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907), α-phenyl-1-(2-phenylethyl)-4-piperidinemethano (M11939), 4-[(2Z)-3-{[2-(dimethylamino)ethoxy]amino}-3-(2-fluorophenyl)prop-2-en-1-ylidene]cyclohexa-2,5-dien-1-one (SR46349B), and pimavanserin], on the phencyclidine (PCP)-induced hyperlocomotor response and cortical 5-HT(2A) receptor levels in C57BL/6J mice. Clozapine and olanzapine, but not haloperidol, induced receptor down-regulation and attenuated PCP-induced locomotor responses. Of the selective 5-HT(2A) antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-HT(2A) receptors and potentiated PCP-hyperlocomotion; the other 5-HT(2A) receptor antagonists were without effect. The significance of these findings with respect to atypical antipsychotic drug action is discussed.read more
Citations
More filters
Journal ArticleDOI
5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology.
Yao Peng,Yao Peng,Yao Peng,John D. McCorvy,Kasper Harpsøe,Katherine Lansu,Shuguang Yuan,Petr Popov,Petr Popov,Lu Qu,Lu Qu,Mengchen Pu,Tao Che,Louise F. Nikolajsen,Louise F. Nikolajsen,Xi Ping Huang,Yiran Wu,Ling Shen,Walden E. Bjørn-Yoshimoto,Kang Ding,Daniel Wacker,Gye Won Han,Jianjun Cheng,Vsevolod Katritch,Vsevolod Katritch,Anders A. Jensen,Michael A. Hanson,Suwen Zhao,David E. Gloriam,Bryan L. Roth,Raymond C. Stevens,Raymond C. Stevens,Zhi-Jie Liu +32 more
TL;DR: This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCR.
Journal ArticleDOI
Identification of novel functionally selective κ-opioid receptor scaffolds.
Kate L. White,Alex P. Scopton,Marie Laure Rives,Ruslan V. Bikbulatov,PR Polepally,Peter Brown,Terrance Kenakin,Jonathan A. Javitch,Jonathan A. Javitch,Jordan K. Zjawiony,BL Roth +10 more
TL;DR: Many of the identified functionally selective ligands are potent selective KOR agonists that are reported to be active in the central nervous system and represent excellent candidates for in vivo studies aiming at determining the behavioral effects mediated by specific KOR-mediated signaling cascades.
Journal ArticleDOI
Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype–targeted drugs
Herbert Y. Meltzer,Bryan L. Roth +1 more
TL;DR: Two recent 5-HT receptor subtype-selective drugs, lorcaserin and pimavanserin, are discussed, which target the 5HT2C and5HT2A receptors and provide new treatments for obesity and Parkinson's disease psychosis, respectively.
Book ChapterDOI
Serotonergic mechanisms as targets for existing and novel antipsychotics
TL;DR: An update of current preclinical and clinical evidence for the role of these five 5-HT receptors in the actions of current APDs and for the development of novel psychotropic drugs is provided.
Journal ArticleDOI
International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function
Nicholas M. Barnes,Gerard P. Ahern,Carine Bécamel,Joël Bockaert,Michael Camilleri,Severine Chaumont-Dubel,Sylvie Claeysen,Kathryn A. Cunningham,Kevin C. Fone,Michael Gershon,Giuseppe Di Giovanni,Nathalie M. Goodfellow,Adam L. Halberstadt,Rachel M. Hartley,Ghérici Hassaine,Katharine Herrick-Davis,Ruud Hovius,Enza Lacivita,Evelyn K. Lambe,Marcello Leopoldo,Finn Olav Levy,Sarah C. R. Lummis,Philippe Marin,Luc Maroteaux,Andrew C. McCreary,David Nelson,John F. Neumaier,Adrian Newman-Tancredi,Hugues Nury,Alexander Roberts,Bryan L. Roth,Anne Roumier,Gareth J. Sanger,Milt Teitler,Trevor Sharp,Carlos M. Villalón,Horst Vogel,Stephanie W. Watts,Daniel Hoyer,Daniel Hoyer +39 more
TL;DR: In this article, a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit, is provided, where appropriate, the utility of therapeutics targeting these receptors.
References
More filters
Journal ArticleDOI
GPCR Engineering Yields High-Resolution Structural Insights into β2-Adrenergic Receptor Function
Daniel M. Rosenbaum,Vadim Cherezov,Michael A. Hanson,Søren G. F. Rasmussen,Foon Sun Thian,Tong Sun Kobilka,Hee Jung Choi,Xiao-Jie Yao,William I. Weis,Raymond C. Stevens,Brian K. Kobilka +10 more
TL;DR: Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of β2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists.
Journal ArticleDOI
Functional Selectivity and Classical Concepts of Quantitative Pharmacology
Jonathan D. Urban,William P. Clarke,Mark von Zastrow,David E. Nichols,Brian K. Kobilka,Harel Weinstein,Jonathan A. Javitch,Bryan L. Roth,Arthur Christopoulos,Patrick M. Sexton,Keith J. Miller,Michael Spedding,Richard B. Mailman +12 more
TL;DR: Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action.
Journal ArticleDOI
Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia
TL;DR: It is proposed that designing selectively non-selective drugs (that is, 'magic shotguns') that interact with several molecular targets will lead to new and more effective medications for a variety of central nervous system disorders.
Journal ArticleDOI
A modification of receptor theory
TL;DR: An attempt has been made to determine the relation between log concentration and effect for acetylcholine and the frog rectus abdominis after blocking the cholinesterase activity of isolated rabbit auricles.
Journal ArticleDOI
Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding
TL;DR: The decrease in the number of receptor sites is most marked for [3H]spiroperidol-labeled serotonin receptors and is characteristic for antidepressants of several classes.
Related Papers (5)
Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs
Miguel Fribourg,José L. Moreno,Terrell Holloway,Davide Provasi,Lia Baki,Rahul Mahajan,Gyu Park,Scott K. Adney,Candice N. Hatcher,Jose M. Eltit,Jeffrey D. Ruta,Laura Albizu,Zheng Li,Adrienne Umali,Jihyun Shim,Alexandre Fabiato,Alexander D. MacKerell,Vladimir Brezina,Stuart C. Sealfon,Marta Filizola,Javier González-Maeso,Diomedes E. Logothetis +21 more