Bioisosteric Replacement of Amides with 1,2,3-Triazoles Improves Dopamine D4 Receptor Ligand Pharmacokinetics

Dopamine D4 receptor (D₄R) signaling affects decision-making, memory formation, cognition, and attention. Previously developed D₄R-selective ligands were metabolically unstable in vivo due to amide bond linker hydrolysis. In this study, analog compounds were synthesized using click chemistry, bioisosterically replacing amides with a 1,2,3-triazole linker. Herein, we report 1,2,3-triazole analogs maintained high D₄R affinity and subtype selectivity but had slightly reduced functional efficacy in cAMP and β-arrestin recruitment assays. Using rat and human liver microsomes to evaluate phase I metabolism, we determined that amide ligands were more metabolically unstable in rat microsomes, and the triazole substitutions enhanced compound stability. Four compounds were evaluated in rat pharmacokinetics studies. In particular, 17 (antagonist) and 18 (low-efficacy partial agonist) had desirable results in plasma half-life and brain exposure measures. These new analogs are suitable for behavioral studies in rats and represent improved molecular tools to further explore D₄R signaling in rodent models.