Hydroxylated decahydroquinolines as ligands for the vesicular acetylcholine transporter: synthesis and biological evaluation.
Analogues of the potent anticholinergic 2-(4-phenylpiperidino)cyclohexanol (vesamicol, 1) in which the cyclohexyl fragment was replaced with an N-acyl or N-alkyl trans-decahydroquinolyl moiety were synthesized and evaluated as potential ligands for the vesicular acetylcholine transporter (VAChT). The binding of compounds, such as 18, 20, and 21, was both stereospecific and of comparable magnitude to that of the closely related vesamicol analogue 2,3-trans-4a, 8a-trans-3-hydroxy-2-(4-phenylpiperidino)-1,2,3,4,5,6,7, 8-decahydronaphthalene (6) which displays subnanomolar affinity for this transporter. However, these compounds also demonstrated high affinities for sigma(1) and sigma(2) receptors and thus failed to show significantly improved selectivity over previously reported vesamicol analogues.
Efange
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University of Minnesota, Minneapolis, Minnesota 55455, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157, USA. efang@maroon.tc.umn.edu
Khare
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Mach
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Parsons
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D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004557:Electric Organ / Q000378:metabolism / Q000648:ultrastructure; D006168:Guinea Pigs; D008024:Ligands; D026901:Membrane Transport Proteins; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000378:metabolism; D013329:Structure-Activity Relationship; D013572:Synaptic Vesicles / Q000378:metabolism*; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D000097605:Sigma-1 Receptor
D000109:Acetylcholine; D002352:Carrier Proteins; D008024:Ligands; D026901:Membrane Transport Proteins; D011804:Quinolines; D017480:Receptors, sigma; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D000097605:Sigma-1 Receptor