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

Jeremy Shonberg, Carmen Klein Herenbrink, Laura Lopez, Arthur Christopoulos, Peter John Scammells, Benvenuto Capuano, Jonathan Robert David Lane

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64 Citations (Scopus)


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-(3,4dihydroisoquinolin-2(1H)-yOethyl)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.
Original languageEnglish
Pages (from-to)9199 - 9221
Number of pages23
JournalJournal of Medicinal Chemistry
Issue number22
Publication statusPublished - 2013

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