title: A structure-activity analysis of biased agonism at the dopamine D2 receptor.
abstract: 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.
authors.affiliation: Medicinal Chemistry, ‡Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Shonberg
authors.forename: Carmen Klein
authors.initials: CK
authors.lastname: Herenbrink
authors.forename: Laura
authors.initials: L
authors.lastname: López
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.forename: Ben
authors.initials: B
authors.lastname: Capuano
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D017448:Receptors, Dopamine D2; C039109:isoquinoline