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A structure-activity analysis of biased agonism at the dopamine D2 receptor.

Shonberg, Jeremy; Herenbrink, Carmen Klein; L�pez, Laura; Christopoulos, Arthur; Scammells, Peter J; Capuano, Ben; Lane, J Robert


Jeremy Shonberg

Carmen Klein Herenbrink

Laura L�pez

Arthur Christopoulos

Peter J Scammells

Ben Capuano

Associate Professor


Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.


Shonberg, J., Herenbrink, C. K., López, L., Christopoulos, A., Scammells, P. J., Capuano, B., & Lane, J. R. (2013). A structure-activity analysis of biased agonism at the dopamine D2 receptor. Journal of Medicinal Chemistry, 56(22), 9199-9221.

Journal Article Type Article
Acceptance Date Aug 26, 2013
Online Publication Date Nov 8, 2013
Publication Date Nov 27, 2013
Deposit Date Apr 22, 2020
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 56
Issue 22
Pages 9199-9221
Public URL
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