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

## TL;DR

This study improves dopamine D4 receptor ligands by replacing amides with triazoles, enhancing stability and brain exposure for better research tools.

## Contribution

Replacing amide linkers with 1,2,3-triazoles improves ligand stability and pharmacokinetics for D4R studies.

## Key findings

- Triazole analogs retained D4R affinity and selectivity but had reduced functional efficacy.
- Triazole substitutions increased metabolic stability in rat liver microsomes.
- Compounds 17 and 18 showed improved plasma half-life and brain exposure in rats.

## Abstract

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.