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Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor

Fyfe, Tim John; Kellam, Barrie; Sykes, David A.; Capuano, Ben; Scammells, Peter J.; Lane, J. Robert; Charlton, Steven J.; Mistry, Shailesh N.

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Tim John Fyfe

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Professor of Medicinal Chemistry

David A. Sykes

Ben Capuano

Peter J. Scammells

Associate Professor

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Professor of Molecular Pharmacology and Drug Discovery


Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side-effects (EPS) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with contrasting kinetic profiles. Haloperidol displays fast association/slow dissociation at the D2R whereas clozapine exhibits relatively slow association/fast dissociation. Recently, we have provided evidence that slow dissociation from the D2R predicts hyperprolactinemia, whereas fast association predicts EPS. Unfortunately, clozapine can cause severe side-effects independent of its D2R action. Our results suggest an optimal kinetic profile for D2R antagonist APDs that avoids EPS. To begin exploring this hypothesis, we conducted a structure-kinetic relationship study of haloperidol and reveal that subtle structural modifications dramatically change binding kinetic rate constants, affording compounds with a clozapine-like kinetic profile. Thus, optimisation of these kinetic parameters may allow development of novel APDs based on the haloperidol scaffold with improved side-effect profiles.

Journal Article Type Article
Acceptance Date Oct 3, 2019
Online Publication Date Oct 3, 2019
Publication Date Nov 14, 2019
Deposit Date Oct 15, 2019
Publicly Available Date Oct 4, 2020
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 62
Issue 21
Pages 9488-9520
Keywords Molecular medicine; Drug discovery
Public URL
Publisher URL
Additional Information This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry
, copyright ©2019 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see


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