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 while retaining their functional activity. Using rat and human liver microsomes to evaluate phase I metabolism, we determined that the metabolic stability of triazole compounds was improved over amide analogs. In particular, 18 is a potent D4R partial agonist, metabolically stable in rat and human liver microsomes, with a half-life (t1/2 ≈ 1 hour) and brain penetration in rats (AUCbrain/plasma > 2.70) that is suitable for behavioral studies. These new analogs represent improved molecular tools to further explore D4R signaling in rodent models.