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Updated: Feb 20, 2026

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Reemplazo bioisostérico de amidas con 1,2,3-triazoles mejora la farmacocinética de ligandos del receptor de dopamina

Mohammad Alkhatib¹, Franziska M Jakobs², John N Hanson³

¹Department of Chemistry & Biochemistry, Department of Biological & Biomedical Sciences, College of Science and Mathematics, Rowan University, 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States.

ACS pharmacology & translational science

|February 19, 2026

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.

Palabras clave:

1,2,3-triazol agonista antagonista bioisóstero receptor de dopamina D4 farmacocinética

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