Pyrrolidine analogues of lobelane: relationship of affinity for the dihydrotetrabenazine binding site with function of the vesicular monoamine transporter 2 (VMAT2)

J Med Chem. 2009 Dec 10;52(23):7878-82. doi: 10.1021/jm900770h.

Abstract

Ring size reduction of the central piperidine ring of lobelane yielded pyrrolidine analogues that showed marked inconsistencies in their ability to bind to the dihydrotetrabenazine (DTBZ) binding site on the vesicular monoamine transporter-2 (VMAT2) and their ability to inhibit VMAT2 function. The structure-activity relationships indicate that structural modification within the pyrrolidine series resulted in analogues that interact with two different sites, i.e., the DTBZ binding site and an alternative site on VMAT2 to inhibit transporter function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Lobeline / analogs & derivatives*
  • Lobeline / chemistry
  • Protein Binding
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism*
  • Pyrrolidines / pharmacology
  • Structure-Activity Relationship
  • Tetrabenazine / analogs & derivatives*
  • Tetrabenazine / metabolism
  • Vesicular Monoamine Transport Proteins / antagonists & inhibitors
  • Vesicular Monoamine Transport Proteins / chemistry*
  • Vesicular Monoamine Transport Proteins / metabolism*

Substances

  • Pyrrolidines
  • Vesicular Monoamine Transport Proteins
  • lobelane
  • dihydrotetrabenazine
  • Lobeline
  • pyrrolidine
  • Tetrabenazine