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 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 G_oBRET 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.