Bioisosteric Replacement of Amides with 1,2,3-Triazoles Improves Dopamine D4 Receptor Ligand Pharmacokinetics
Year: 2026
Type: article
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 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.
Authors: Mohammad Alkhatib, Franziska M. Jakobs, John N. Hanson, Ashley N. Nilson, Amy E. Moritz, Tian Li, Afua B. Faibille, Lindsay A. Bourn, Peter A. Ramdhan, Joseph Ricchezza, Shannon Jordan, Diandra Panasis, Norman Nguyen, Nitish Kasarla, Bryant Wang, Sergio Sola Garcia, Julianna Saez, James Paule, Chae Bin Lee, Rana Rais, Barbara S. Slusher, David R. Sibley, Chenglong Li, Thomas M. Keck, Comfort A. Boateng
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: National Science Foundation, Johns Hopkins University, High Point University, Rowan University, National Institutes of Health, University of North Carolina at Chapel Hill, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Division of Chemistry
Awards: G102925328, G1232909846, G2476831334, MRI: Acquisition of a 400 MHz Nuclear Magnetic Resonance (NMR) Spectrometer to Support Undergraduate Research at High Point University, Low-Efficacy Dopamine D4 Receptor Partial Agonists for Cocaine Addiction, G4364667842, G4950536974, G7009490193, Molecular And Pharmacological Studies Of Dopamine Receptors, U-Rise at Rowan University, Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
OpenAlex ID: W7120175790