Subtle Modifications to the Indole-2-carboxamide Motif of the Negative Allosteric Modulator <i>N</i>‑((<i>trans</i>)‑4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1<i>H</i>)‑yl)ethyl)cyclohexyl)‑1<i>H</i>‑indole-2-carboxamide (SB269652) Yield Dramatic Changes in Pharmacological Activity at the Dopamine D₂ Receptor

SB269652 (1) is a negative allosteric modulator of the dopamine D2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of “second generation” analogues of 1 whereby subtle modifications to the indole-2-carboxamide motif confer dramatic changes in functional affinity (5000-fold increase), cooperativity (100-fold increase), and a novel action to modulate dopamine efficacy. Thus, structural changes to this region of 1 allows the generation of a novel set of analogues with distinct pharmacological properties.