Acyclic analogues of 2-(4-phenylpiperidino)cyclohexanol (vesamicol): conformationally mobile inhibitors of vesicular acetylcholine transport.
Several 1,3-disubstituted propan-2-ols and one alpha,beta-disubstituted ethanol (11i) were synthesized and evaluated as potential acyclic mimics of the vesicular acetylcholine transport inhibitor 2-(4-phenylpiperidinyl)cyclohexanol (1, vesamicol, AH5183). Analogues containing the 4-phenylpiperidyl fragment (11a, 11b) were more potent than those containing the 4-phenylpiperazyl moiety (11e, 11f). Substitution at the second terminal carbon of the propyl (or ethyl) fragment with simple lipophilic aryl substituents yielded potent inhibitors of vesicular acetylcholine storage, including (-)-11a and d-11i, which are equipotent with vesamicol. However, the activity of analogues containing bicyclic aryl groups was susceptible to aryl substitution patterns (11g vs 11h), indicating a definite receptor site topography. In addition, the inhibitory activity of these acyclic analogues was enantioselective, exhibiting a preference, similar to the parent vesamicol, for the levorotatory isomer [(-)-11a vs (+)-11a]. Therefore, the simple lipophilic acyclic vicinal amino alcohols may successfully mimic the biological activity of vesamicol.
Efange
S M
SM
Department of Radiology, University of Minnesota, Minneapolis 55455.
Michelson
R H
RH
Dutta
A K
AK
Parsons
S M
SM
D000109:Acetylcholine / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D008968:Molecular Conformation; D015394:Molecular Structure; D010276:Parasympatholytics / Q000138:chemical synthesis / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010276:Parasympatholytics; D010880:Piperidines; C006189:vesamicol; D000109:Acetylcholine