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The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions

Draper-Joyce, Christopher J.; Verma, Ravi Kumar; Michino, Mayako; Shonberg, Jeremy; Kopinathan, Anitha; Herenbrink, Carmen; Scammells, Peter J.; Capuano, Ben; Abramyan, Ara M; Thal, David M.; Javitch, Jonathan A.; Christopoulos, Arthur; Shi, Lei; Lane, J. Robert


Christopher J. Draper-Joyce

Ravi Kumar Verma

Mayako Michino

Jeremy Shonberg

Anitha Kopinathan

Carmen Herenbrink

Peter J. Scammells

Ben Capuano

Ara M Abramyan

David M. Thal

Jonathan A. Javitch

Arthur Christopoulos

Lei Shi

Associate Professor


© 2018 The Author(s). Sodiumions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D 2 receptor (D 2 R). Experimental and computational evidences have revealed that this effect is mediated by the binding of Na + to a conserved site located beneath the orthosteric binding site (OBS). SB269652 acts as a negative allosteric modulator (NAM) of the D 2 R that adopts an extended bitopic pose, in which the tetrahydroisoquinoline moiety interacts with the OBS and the indole-2-carboxamide moiety occupies a secondary binding pocket (SBP). In this study, we find that the presence of a Na + within the conserved Na + -binding pocket is required for the action of SB269652. Using fragments of SB269652 and novel full-length analogues, we show that Na + is required for the high affinity binding of the tetrahydroisoquinoline moiety within the OBS, and that the interaction of the indole-2-carboxamide moiety with the SBP determines the degree of Na + -sensitivity. Thus, we extend our understanding of the mode of action of this novel class of NAM by showing it acts synergistically with Na + to modulate the binding of orthosteric ligands at the D 2 R, providing opportunities for fine-tuning of modulatory effects in future allosteric drug design efforts.


Draper-Joyce, C. J., Verma, R. K., Michino, M., Shonberg, J., Kopinathan, A., Herenbrink, C., …Lane, J. R. (2018). The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions. Scientific Reports, 8(1), Article 1208.

Journal Article Type Article
Acceptance Date Dec 19, 2017
Online Publication Date Jan 19, 2018
Publication Date Jan 19, 2018
Deposit Date Apr 22, 2020
Publicly Available Date Jun 8, 2020
Journal Scientific Reports
Print ISSN 2045-2322
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Issue 1
Article Number 1208
Public URL
Publisher URL


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