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

Mu Fa Zou, Thomas M. Keck, Vivek Kumar, Prashant Donthamsetti, Mayako Michino, Caitlin Burzynski, Catherine Schweppe, Alessandro Bonifazi, R. Benjamin Free, David R. Sibley, Aaron Janowsky, Lei Shi, Jonathan A. Javitch, Amy Hauck Newman

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 [3H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [3H]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.

Original languageEnglish (US)
Pages (from-to)2973-2988
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number7
DOIs
StatePublished - Apr 28 2016

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Dopamine D3 Receptors
Dopamine D2 Receptors
Binding Sites
U 95666E
hydroxide ion
7-hydroxy-2-N,N-dipropylaminotetralin
N,N-dipropyl-2-aminotetralin

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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. / Zou, Mu Fa; Keck, Thomas M.; Kumar, Vivek; Donthamsetti, Prashant; Michino, Mayako; Burzynski, Caitlin; Schweppe, Catherine; Bonifazi, Alessandro; Free, R. Benjamin; Sibley, David R.; Janowsky, Aaron; Shi, Lei; Javitch, Jonathan A.; Newman, Amy Hauck.

In: Journal of Medicinal Chemistry, Vol. 59, No. 7, 28.04.2016, p. 2973-2988.

Research output: Contribution to journalArticle

Zou, MF, Keck, TM, Kumar, V, Donthamsetti, P, Michino, M, Burzynski, C, Schweppe, C, Bonifazi, A, Free, RB, Sibley, DR, Janowsky, A, Shi, L, Javitch, JA & Newman, AH 2016, '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', Journal of Medicinal Chemistry, vol. 59, no. 7, pp. 2973-2988. https://doi.org/10.1021/acs.jmedchem.5b01612
Zou, Mu Fa ; Keck, Thomas M. ; Kumar, Vivek ; Donthamsetti, Prashant ; Michino, Mayako ; Burzynski, Caitlin ; Schweppe, Catherine ; Bonifazi, Alessandro ; Free, R. Benjamin ; Sibley, David R. ; Janowsky, Aaron ; Shi, Lei ; Javitch, Jonathan A. ; Newman, Amy Hauck. / 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. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 7. pp. 2973-2988.
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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 [3H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [3H]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.",
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T1 - 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

AU - Zou, Mu Fa

AU - Keck, Thomas M.

AU - Kumar, Vivek

AU - Donthamsetti, Prashant

AU - Michino, Mayako

AU - Burzynski, Caitlin

AU - Schweppe, Catherine

AU - Bonifazi, Alessandro

AU - Free, R. Benjamin

AU - Sibley, David R.

AU - Janowsky, Aaron

AU - Shi, Lei

AU - Javitch, Jonathan A.

AU - Newman, Amy Hauck

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N2 - 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 [3H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [3H]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.

AB - 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 [3H]7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [3H]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.

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