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

Novel 1-, 5-, and 8-substituted analogues of sumanirole (1), a dopamine D-2/D-3 receptor (D2R/D3R) agonist, were synthesized. Binding affinities at both D2R and D3R were higher when determined in competition with the agonist radioligand [H-3]7-hydroxy-N,N-dipropy1-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [H-3]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 G(o)BRET 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.