Synthesis and in vitro biological evaluation of carbonyl group-containing analogues for σ1 receptors

Wei Wang, Jinquan Cui, Xiaoxia Lu, Prashanth K. Padakanti, Jinbin Xu, Stanley M. Parsons, Robert R. Luedtke, Nigam P. Rath, Zhude Tu

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


To identify the ligands for σ1 receptors that are potent and selective, analogues of prezamicol and trozamicol scaffolds of carbonyl-containing vesicular acetylcholine transporter (VAChT) inhibitors were explored. Of the 23 analogues synthesized and tested, 5 displayed very high affinity for σ1 (Ki = 0.48-4.05 nM) and high selectivity for σ1 relative to σ2 receptors (σ12 selectivity of >749-fold). Four of the five compounds (14a, 14b, 14c, and 14e) showed very low affinity for VAChT (Ki > 290 nM), and the fifth compound (14g) showed moderate affinity for VAChT (Ki = 44.2 nM). The compound [1′-(4- fluorobenzyl)-3′-hydroxy[1,4′]bipiperidinyl-4-yl]-(4-fluorophenyl) methanone (14a) displayed very high affinity and selectivity for σ1 receptor (Ki = 0.48 nM, σ1/ σ2 > 3600). All four of these most promising compounds (14a, 14b, 14c, and 14e) can be radiosynthesized with fluorine-18 or carbon-11, which will allow further evaluation of their properties as PET probes for imaging σ1 receptor in vivo.

Original languageEnglish
Pages (from-to)5362-5372
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number15
StatePublished - 11 Aug 2011


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