Hydroxylated Decahydroquinolines as Ligands for the Vesicular Acetylcholine Transporter:  Synthesis and Biological Evaluation

• Published in: Journal of medicinal chemistry Vol. 42; no. 15; pp. 2862 - 2869
• Main Authors: Efange, Simon M. N, Khare, Anil B, Mach, Robert H, Parsons, Stanley M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 29.07.1999; Amer Chemical Soc
• Subjects: Acetylcholine - metabolism; Animals; Biological and medical sciences; Carrier Proteins - metabolism; Chemistry, Medicinal; Cholinergic system; Electric Organ - metabolism; Electric Organ - ultrastructure; Guinea Pigs; Life Sciences & Biomedicine; Ligands; Medical sciences; Membrane Transport Proteins; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - metabolism; Radioligand Assay; Receptors, sigma - metabolism; Science & Technology; Sigma-1 Receptor; Structure-Activity Relationship; Synaptic Vesicles - metabolism; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins; SYNAPTIC VESICLES; VESAMICOL RECEPTOR-LIGAND; CAENORHABDITIS-ELEGANS; RAT; ANALOGS; 2 CHOLINERGIC MARKERS; POSITRON EMISSION TOMOGRAPHY; 2-(4-PHENYLPIPERIDINO)CYCLOHEXANOL VESAMICOL; EXPRESSION; BINDING; Aminoalcohol; Nitrogen heterocycle; Rodentia; Central nervous system; Quinoline derivatives; Alcohol; In vitro; Vertebrata; Mammalia; Guinea pig; Structure activity relation; Membrane transport; Trans stereoisomer; Neurotransmitter; Carboxamide; Stereospecificity; Acetylcholine; Chemical synthesis; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980560x

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 σ1 and σ2 receptors and thus failed to show significantly improved selectivity over previously reported vesamicol analogues.