Synthesis and in vitro evaluation of α-synuclein ligands.
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)=32.10 ± 1.25 nM) and compounds 11d, 16a and16b have moderate affinity to α-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 α-synuclein.
Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Boulevard, St. Louis, MO 63110, USA.
Lihai
L
Yu
Jinquan
J
Cui
Prashanth K
PK
Padakanti
Laura
L
Engel
Devika P
DP
Bagchi
Paul T
PT
Kotzbauer
Zhude
Z
Tu
D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D015394:Molecular Structure; D010640:Phenothiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors*
D008024:Ligands; D010640:Phenothiazines; D051844:alpha-Synuclein