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.

Abstract

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.

Citation

Fyfe, T. J., Kellam, B., Sykes, D. A., Capuano, B., Scammells, P. J., Lane, J. R., Charlton, S. J., & Mistry, S. N. (2019). Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor. Journal of Medicinal Chemistry, 62(21), 9488-9520. https://doi.org/10.1021/acs.jmedchem.9b00864

• 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
• DOI: https://doi.org/10.1021/acs.jmedchem.9b00864
• Keywords: Molecular medicine; Drug discovery
• Public URL: https://nottingham-repository.worktribe.com/output/2836712
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00864
• 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 https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b00864
• Contract Date: Oct 15, 2019