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J Med Chem. 2016 Apr 14;59(7):2973-88. doi: 10.1021/acs.jmedchem.5b01612. Epub 2016 Apr 1.

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.

Author information

1
Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons , New York, New York 10027, United States.
2
Division of Molecular Therapeutics, New York State Psychiatric Institute , New York, New York 10032, United States.
3
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.
4
Research & Development Service, Veterans Affairs Portland Health Care System , Portland, Oregon 97239, United States.
5
Department of Psychiatry and Behavioral Neuroscience, School of Medicine and Methamphetamine Abuse Research Center, Oregon Health & Science University , Portland, Oregon 97239, United States.
6
Department of Physiology and Biophysics and the Institute for Computational Biomedicine, Weill Medical College of Cornell University , New York, New York 10065, United States.

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.

PMID:
27035329
PMCID:
PMC4915350
DOI:
10.1021/acs.jmedchem.5b01612
[Indexed for MEDLINE]
Free PMC Article

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