Synthesis and in vitro biological evaluation of carbonyl group-containing inhibitors of vesicular acetylcholine transporter

Simon M.N. Efange, Anil B. Khare, Krystyna Von Hohenberg, Robert H. MacH, Stanley M. Parsons, Zhude Tu

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23 Scopus citations

Abstract

To identify selective high-affinity inhibitors of the vesicular acetylcholine transporter (VAChT), we have interposed a carbonyl group between the phenyl and piperidyl groups of the prototypical VAChT ligand vesamicol and its more potent analogues benzovesamicol and 5-aminobenzovesamicol. Of 33 compounds synthesized and tested, 6 display very high affinity for VAChT (K i, 0.25-0.66 nM) and greater than 500-fold selectivity for VAChT over σ1 and σ2 receptors. Twelve compounds have high affinity (Ki, 1.0-10 nM) and good selectivity for VAChT. Furthermore, 3 halogenated compounds, namely, trans-3-[4-(4-fluorobenzoyl) piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28b) (Ki = 2.7 nM, VAChT/sigma selectivity index = 70), trans-3-[4-(5-iodothienylcarbonyl) piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28h) (Ki = 0.66 nM, VAChT/sigma selectivity index = 294), and 5-amino-3-[4-(p-fluorobenzoyl) piperidinyl]-2-hydroxy-1,2,3,4,-tetrahydronaphthalene (30b) (Ki = 2.40 nM, VAChT/sigma selectivity index = 410) display moderate to high selectivity for VAChT. These three compounds can be synthesized with the corresponding radioisotopes so as to serve as PET/SPECT probes for imaging the VAChT in vivo.

Original languageEnglish
Pages (from-to)2825-2835
Number of pages11
JournalJournal of Medicinal Chemistry
Volume53
Issue number7
DOIs
StatePublished - Apr 8 2010

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