Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands

Thomas M. Keck, Ashwini K. Banala, Rachel D. Slack, Caitlin Burzynski, Alessandro Bonifazi, Oluyomi M. Okunola-Bakare, Jeffrey R. Deschamps, Rana Rais, Barbara S. Slusher, Amy Hauck Newman

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, Parkinson's disease, restless leg syndrome, and drug addiction. A common molecular template used in the development of D3R-selective antagonists and partial agonists incorporates a butylamide linker between two pharmacophores, a phenylpiperazine moiety and an extended aryl ring system. The series of compounds described herein incorporates a change to that chemical template, replacing the amide functional group in the linker chain with a 1,2,3-triazole group. Although the amide linker in the 4-phenylpiperazine class of D3R ligands has been previously deemed critical for high D3R affinity and selectivity, the 1,2,3-triazole moiety serves as a suitable bioisosteric replacement and maintains desired D3R-binding functionality of the compounds. Additionally, using mouse liver microsomes to evaluate CYP450-mediated phase I metabolism, we determined that novel 1,2,3-triazole-containing compounds modestly improves metabolic stability compared to amide-containing analogues. The 1,2,3-triazole moiety allows for the modular attachment of chemical subunit libraries using copper-catalyzed azide-alkyne cycloaddition click chemistry, increasing the range of chemical entities that can be designed, synthesized, and developed toward D3R-selective therapeutic agents.

Original languageEnglish (US)
Pages (from-to)4000-4012
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number14
DOIs
StatePublished - Jun 11 2015

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmaceutical Science
  • Organic Chemistry

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