title: Synthesis and in vitro biological evaluation of carbonyl group-containing analogues for σ1 receptors.
abstract: To identify the ligands for σ(1) 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 σ(1) (K(i) = 0.48-4.05 nM) and high selectivity for σ(1) relative to σ(2) receptors (σ(1)/σ(2) selectivity of >749-fold). Four of the five compounds (14a, 14b, 14c, and 14e) showed very low affinity for VAChT (K(i) > 290 nM), and the fifth compound (14g) showed moderate affinity for VAChT (K(i) = 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 σ(1) receptor (K(i) = 0.48 nM, σ(1)/σ(2) > 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 σ(1) receptor in vivo.
authors: Department of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
authors: Wei
authors: W
authors: Wang
authors: Jinquan
authors: J
authors: Cui
authors: Xiaoxia
authors: X
authors: Lu
authors: Prashanth K
authors: PK
authors: Padakanti
authors: Jinbin
authors: J
authors: Xu
authors: Stanley M
authors: SM
authors: Parsons
authors: Robert R
authors: RR
authors: Luedtke
authors: Nigam P
authors: NP
authors: Rath
authors: Zhude
authors: Z
authors: Tu
mesh_terms: D000818:Animals; D006168:Guinea Pigs; D006801:Humans; D016716:PC12 Cells; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017480:Receptors, sigma / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D050494:Vesicular Acetylcholine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010880:Piperidines; D017480:Receptors, sigma; D050494:Vesicular Acetylcholine Transport Proteins