Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors
David A. Sykes,Holly Moore,Lisa A. Stott,Nicholas D. Holliday,Jonathan A. Javitch,J. Robert Lane,Steven J. Charlton +6 more
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TL;DR: Time-resolved FRET is used to measure binding kinetics, and it is shown that side effects correlate with drug association rates to the D2 receptor, while dissociation rates correlate with prolactin elevation.
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Abstract: Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 receptor. However, support for this hypothesis is limited to a relatively small number of observations made across several decades and under different experimental conditions. Here we show that association rates, but not dissociation rates, correlate with EPS. We measured the kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay, and correlated these properties with their EPS and prolactin-elevating liabilities at therapeutic doses. EPS are robustly predicted by a rebinding model that considers the microenvironment of postsynaptic D2 receptors and integrates association and dissociation rates to calculate the net rate of reversal of receptor blockade. Thus, optimizing binding kinetics at the D2 receptor may result in APDs with improved therapeutic profile.
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The Lancet Psychiatry Commission: a blueprint for protecting physical health in people with mental illness
Joseph Firth,Joseph Firth,Joseph Firth,Najma Siddiqi,Ai Koyanagi,Ai Koyanagi,Ai Koyanagi,Dan Siskind,Simon Rosenbaum,Cherrie Galletly,Stephanie Allan,Constanza Caneo,Rebekah Carney,André F. Carvalho,André F. Carvalho,Mary Lou Chatterton,Christoph U. Correll,Christoph U. Correll,Jackie Curtis,Fiona Gaughran,Fiona Gaughran,Adrian H. Heald,Adrian H. Heald,Adrian H. Heald,Erin Hoare,Sarah E Jackson,Steve Kisely,Steve Kisely,Karina Lovell,Mario Maj,Patrick D. McGorry,Cathrine Mihalopoulos,Hannah Myles,Brian O'Donoghue,Toby Pillinger,Jerome Sarris,Jerome Sarris,Felipe Barreto Schuch,David Shiers,Lee Smith,Marco Solmi,Shuichi Suetani,Shuichi Suetani,Johanna Taylor,Scott B Teasdale,Graham Thornicroft,John Torous,Tim Usherwood,Tim Usherwood,Davy Vancampfort,Nicola Veronese,Philip B. Ward,Alison R. Yung,Alison R. Yung,Eoin Killackey,Brendon Stubbs,Brendon Stubbs +56 more
TL;DR: This Commission summarises advances in understanding on the topic of physical health in people with mental illness, and presents clear directions for health promotion, clinical care, and future research.
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Mechanisms of signalling and biased agonism in G protein-coupled receptors
Denise Wootten,Arthur Christopoulos,Maria Marti-Solano,M. Madan Babu,Patrick M. Sexton,Patrick M. Sexton +5 more
TL;DR: Increasing molecular and structural understanding of biased agonism offers the possibility of designing improved GPCR-targeting drugs, and refined classification of drugs according to their pharmacodynamic profiles, which can be linked to receptor structure and predictions of preclinical drug efficacy.
602
Structure of the D2 dopamine receptor bound to the atypical antipsychotic drug risperidone.
TL;DR: The crystal structure of DRD2–risperidone structure reveals an unexpected mode of antipsychotic drug binding to dopamine receptors, and highlights structural determinants that are essential for the actions of ris peridone and related drugs atDRD2.
Molecular targets of atypical antipsychotics: From mechanism of action to clinical differences.
Stefano Aringhieri,M. Carli,Shivakumar Kolachalam,Valeria Verdesca,Enrico Cini,Mario Rossi,Peter J. McCormick,Giovanni Corsini,Roberto Maggio,Marco Scarselli +9 more
TL;DR: This review revisits previous and current findings within the class of AAPs and highlights the differences in terms of receptor properties and clinical activities among them, and proposes a continuum spectrum of “atypia” that begins with risperidone (the least atypical) to clozapine (the most atypial), while all the other AAPs fall within the extremes of this spectrum.
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Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain.
TL;DR: An outlook on current research about the metabolic disturbances provoked by SGAs is given, with a particular focus on whole-body glucose homeostasis disturbances induced independently of AIWG, lipid dysregulation or adipose tissue disturbances.
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TL;DR: A meta-analysis of randomised controlled trials to compare the effects of second-generation antipsychotic drugs in patients with schizophrenia provided data for individualised treatment based on efficacy, side-effects, and cost.
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Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values.
TL;DR: The pKi values of 13 reference typical and 7 reference atypical antipsychotic drugs (APDs) for rat striatal dopamine D-1 and D-2 receptors binding sites and cortical serotonin (5-HT2) receptor binding sites were determined.
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Does Fast Dissociation From the Dopamine D2 Receptor Explain the Action of Atypical Antipsychotics?: A New Hypothesis
Shitij Kapur,Philip Seeman +1 more
TL;DR: It is predicted that the atypical antipsychotic effect can be produced by appropriate modulation of the D(2) receptor alone; the blockade of other receptors is neither necessary nor sufficient.
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