Synthesis and in vitro evaluation of α-synuclein ligands

Lihai Yu, Jinquan Cui, Prashanth K. Padakanti, Laura Engel, Devika P. Bagchi, Paul T. Kotzbauer, Zhude Tu

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Accumulation of misfolded α-synuclein in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson's disease (PD). To identify ligands having high binding potency toward aggregated α-synuclein, we synthesized a series of phenothiazine derivatives and assessed their binding affinity to recombinant α-synuclein fibrils using a fluorescent thioflavin T competition assay. Among 16 new analogues, the in vitro data suggest that compound 11b has high affinity to α-synuclein fibrils (Ki = 32.10 ± 1.25 nM) and compounds 11d, 16a and16b have moderate affinity to α-synuclein fibrils (Ki ≈ 50-100 nM). Further optimization of the structure of these analogues may yield compounds with high affinity and selectivity for aggregated α-synuclein.

Original languageEnglish
Pages (from-to)4625-4634
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number15
DOIs
StatePublished - Aug 1 2012

Keywords

  • Fluorescence
  • Lewy bodies
  • Parkinson's disease
  • Phenothiazine
  • α-Synuclein

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