title: Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2Receptor (D2R) Biased Agonism.
abstract: The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound 19 was identified as a new lead for its selective D2G-protein biased agonism with an EC50in the subnanomolar range. Structure-activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus β-arrestin recruitment in D2R-BRET functional assays.
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yano
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Ellenberger
authors.affiliation: Structural Biology Unit, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Muller
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Mu-Fa
authors.initials: MF
authors.lastname: Zou
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Ning Sheng
authors.initials: NS
authors.lastname: Cai
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Guerrero
authors.affiliation: Structural Biology Unit, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Amina S
authors.initials: AS
authors.lastname: Woods
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health , 333 Cassell Drive, Baltimore, Maryland 21224, United States.
authors.forename: Amy Hauck
authors.identifier: 0000-0001-9065-4072
authors.initials: AH
authors.lastname: Newman
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000737:chemistry* / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D018491:Dopamine Agonists; D017448:Receptors, Dopamine D2; D000071557:beta-Arrestins; C108539:U 95666E; D000242:Cyclic AMP; D019204:GTP-Binding Proteins