- 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
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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.
- 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
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p. 2973 - 2988
(2016/05/19)
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- Heterocyclic amines having central nervous system activity
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Tricyclic nitrogen containing compounds, having central nervous system activity of the following structural formula: STR1 and pharmaceutically acceptable salts thereof wherein R1, R2, and R3 are independently hydrogen, C1-6 alkyl, alkenyl, or alkynyl, C3-10 cycloalkyl, or R1 and R2 are joined to form a C3-7 cyclic amine which can contain additional heteroatoms; X is hydrogen, C1-6 alkyl halogen, hydroxy, alkoxy, cyano, carboxamide, carboxyl, or carboalkoxyl; A is SO2, N, CH, CH2, CHCH3, C=O, C=S, C-SCH3, C=NH, C-NH2, C-NHCH3, C--NHCOOCH3, or C--NHCN. B is CH2, CH, C=O, N, NH or N--CH3 ; n is 0 or 1; and D is CH, CH2, C=O, O, N, NH or N--CH3. These new compounds are suitable for treating schizophrenia, Parkinson's disease, anxiety, depression or as compounds for lowering blood pressure in animal or human hosts.
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- Dopaminergic andSerotonergic Activities of Imidazoquinolines and Related Compounds
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The synthesis of 5-(dipropylamino)-5,6-dihydro-4H-imidazoquinolin-2(1H)-one (5), a potent dopamine D2 agonist showing high dopamine/serotonin (5HT1A) selectivity, is described.Dopaminerig activity is associated with the (R)-enantiomer
- Moon, Malcolm W.,Morris, Jeanette K.,Heier, Richard F.,Chidester, Connie G.,Hoffmann, William E.,et al.
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p. 1076 - 1092
(2007/10/02)
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