Synthesis and evaluation of in vitro bioactivity for vesicular acetylcholine transporter inhibitors containing two carbonyl groups.
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.
Department of Radiology, Washington University, St. Louis, MO 63110, United States. tuz@mir.wustl.edu
Zhude
Z
Tu
Wei
W
Wang
Jinquan
J
Cui
Xiang
X
Zhang
Xiaoxia
X
Lu
Jinbin
J
Xu
Stanley M
SM
Parsons
D000588:Amines / Q000737:chemistry; D002250:Carbon Radioisotopes / Q000737:chemistry; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D007659:Ketones / Q000737:chemistry*; D007700:Kinetics; D010880:Piperidines / Q000737:chemistry; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D050494:Vesicular Acetylcholine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000588:Amines; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D007659:Ketones; D010880:Piperidines; D019275:Radiopharmaceuticals; D050494:Vesicular Acetylcholine Transport Proteins