Synthesis and evaluation of in vitro bioactivity for vesicular acetylcholine transporter inhibitors containing two carbonyl groups

Zhude Tu, Wei Wang, Jinquan Cui, Xiang Zhang, Xiaoxia Lu, Jinbin Xu, Stanley M. Parsons

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

To identify selective high-affinity ligands for the vesicular acetylcholine transporter (VAChT), we have incorporated a carbonyl group into the structures of trozamicol and prezamicol scaffolds, and also converted the secondary amines of the piperidines of trozamicols and prezamicols into amides. Of 18 new racemic compounds, 4 compounds displayed high affinity for VAChT (K i = 10-20 nM) and greater than 300-fold selectivity for VAChT over σ 1 and σ 2 receptors, namely (4-(4-fluorobenzoyl)-4′-hydroxy- [1,3′-bipiperidin]-1′-yl)(3-methylthiophen-2-yl)methanone oxalate (9g) (K i-VAChT = 11.4 nM, VAChT/σ 1 = 1063, VAChT/σ 2 = 370), (1′-benzoyl-4′-hydroxy-[1, 3′-bipiperidin]-4-yl)(4-methoxyphenyl)methanone oxalate (10c) (K i-VAChT = 15.4 nM, VAChT/σ 1 = 374, VAChT/σ 2 = 315), (4′-hydroxy-1′-(thiophene-2- carbonyl)-[1,3′-bipiperidin]-4-yl)(4-methoxyphenyl)methanone oxalate (10e) (K i-VAChT = 19.0 nM, VAChT/σ 1 = 1787, VAChT/σ 2 = 335), and (4′-hydroxy-1′-(3- methylthiophene-2-carbonyl)-[1,3′-bipiperidin]-4-yl)(4-methoxyphenyl) methanone oxalate (10g) (K i-VAChT = 10.2 nM, VAChT/σ 1 = 1500, VAChT/σ 2 = 2030). These four compounds can be radiosynthesized with C-11 or F-18 to validate their possibilities of serving as PET probes for quantifying the levels of VAChT in vivo.

Original languageEnglish
Pages (from-to)4422-4429
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number14
DOIs
StatePublished - Jul 15 2012

Keywords

  • CNS disorders
  • Parkinson's disease
  • VAChT
  • Vesamciol
  • σ Receptor

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