Acyclic Analogues of 2-(4-phenylpiperidino)cyclohexanol (Vesamicol): Conformationally Mobile Inhibitors of Vesicular Acetylcholine Transport

J Med Chem. 1991 Aug;34(8):2638-43. doi: 10.1021/jm00112a044.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Biological Transport / drug effects
  • Chemical Phenomena
  • Chemistry
  • Molecular Conformation
  • Molecular Structure
  • Parasympatholytics / chemical synthesis
  • Parasympatholytics / pharmacology*
  • Piperidines / chemistry*
  • Piperidines / pharmacology
  • Structure-Activity Relationship

Substances

  • Parasympatholytics
  • Piperidines
  • vesamicol
  • Acetylcholine