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 a s potential ligands for the vesicular acetylcholine transporter (VAChT). Th e 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-dec ahydronaphthalene (6) which displays subnanomolar affinity for this transpo rter. However, these compounds also demonstrated high affinities for sigma( 1) and sigma(2) receptors and thus failed to show significantly improved se lectivity over previously reported vesamicol analogues.