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Synthesis and in vitro evaluation of ?-synuclein ligands.

ABSTRACT: Accumulation of misfolded ?-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 ?-synuclein, we synthesized a series of phenothiazine derivatives and assessed their binding affinity to recombinant ?-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 ?-synuclein fibrils (K(i)=32.10 ± 1.25 nM) and compounds 11d, 16a and16b have moderate affinity to ?-synuclein fibrils (K(i)?50-100 nM). Further optimization of the structure of these analogues may yield compounds with high affinity and selectivity for aggregated ?-synuclein.

SUBMITTER: Yu L

PROVIDER: S-EPMC3401268 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Synthesis and in vitro evaluation of α-synuclein ligands.

Yu Lihai L Cui Jinquan J Padakanti Prashanth K PK Engel Laura L Bagchi Devika P DP Kotzbauer Paul T PT Tu Zhude Z

Bioorganic & medicinal chemistry 20120619 15

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 (K(i)=3 ...[more]

PMID: 22789706

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