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Synthesis and in Vitro Biological Evaluation of Carbonyl Group-Containing Analogues for σ1 Receptors

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journal contribution
posted on 11.08.2011, 00:00 by Wei Wang, Jinquan Cui, Xiaoxia Lu, Prashanth K. Padakanti, Jinbin Xu, Stanley M. Parsons, Robert R. Luedtke, Nigam P. Rath, Zhude Tu
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, σ12 > 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.

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