title: Novel Analogues of (R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (Sumanirole) Provide Clues to Dopamine D2/D3 Receptor Agonist Selectivity.
abstract: Novel 1-, 5-, and 8-substituted analogues of sumanirole (1), a dopamine D2/D3 receptor (D2R/D3R) agonist, were synthesized. Binding affinities at both D2R and D3R were higher when determined in competition with the agonist radioligand [(3)H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [(3)H]N-methylspiperone. Although 1 was confirmed as a D2R-preferential agonist, its selectivity in binding and functional studies was lower than previously reported. All analogues were determined to be D2R/D3R agonists in both GoBRET and mitogenesis functional assays. Loss of efficacy was detected for the N-1-substituted analogues at D3R. In contrast, the N-5-alkyl-substituted analogues, and notably the n-butyl-arylamides (22b and 22c), all showed improved affinity at D2R over 1 with neither a loss of efficacy nor an increase in selectivity. Computational modeling provided a structural basis for the D2R selectivity of 1, illustrating how subtle differences in the highly homologous orthosteric binding site (OBS) differentially affect D2R/D3R affinity and functional efficacy.
authors.forename: Mu-Fa
authors.initials: MF
authors.lastname: Zou
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Keck
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons , New York, New York 10027, United States.|Division of Molecular Therapeutics, New York State Psychiatric Institute , New York, New York 10032, United States.
authors.forename: Prashant
authors.initials: P
authors.lastname: Donthamsetti
authors.forename: Mayako
authors.initials: M
authors.lastname: Michino
authors.forename: Caitlin
authors.initials: C
authors.lastname: Burzynski
authors.forename: Catherine
authors.initials: C
authors.lastname: Schweppe
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.affiliation: Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , 5625 Fishers Lane, Room 4S-04, Bethesda, Maryland 20892-9405, United States.
authors.forename: R Benjamin
authors.initials: RB
authors.lastname: Free
authors.affiliation: Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , 5625 Fishers Lane, Room 4S-04, Bethesda, Maryland 20892-9405, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Sibley
authors.affiliation: Research & Development Service, Veterans Affairs Portland Health Care System , Portland, Oregon 97239, United States.|Department of Psychiatry and Behavioral Neuroscience, School of Medicine and Methamphetamine Abuse Research Center, Oregon Health & Science University , Portland, Oregon 97239, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Janowsky
authors.affiliation: Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Medical College of Cornell University , New York, New York 10065, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons , New York, New York 10027, United States.|Division of Molecular Therapeutics, New York State Psychiatric Institute , New York, New York 10032, United States.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry*; D001665:Binding Sites; D016466:CHO Cells; D060326:Chemistry Techniques, Synthetic; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; C581293:DRD2 protein, human; D008024:Ligands; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C108539:U 95666E