Lobelane analogues containing 4-hydroxy and 4-(2-fluoroethoxy) aromatic substituents: Potent and selective inhibitors of [(3)H]dopamine uptake at the vesicular monoamine transporter-2

Bioorg Med Chem Lett. 2016 May 15;26(10):2422-2427. doi: 10.1016/j.bmcl.2016.03.119. Epub 2016 Apr 1.

Abstract

A series of lobelane and GZ-793A analogues that incorporate aromatic 4-hydroxy and 4-(2-fluoroethoxy) substituents were synthesized and evaluated for inhibition of [(3)H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and the dopamine transporter (DAT), and [(3)H]serotonin uptake at the serotonin transporter (SERT). Most of these compounds exhibited potent inhibition of DA uptake at VMAT2 in the nanomolar range (Ki=30-70nM). The two most potent analogues, 7 and 14, both exhibited a Ki value of 31nM for inhibition of VMAT2. The lobelane analogue 14, incorporating 4-(2-fluoroethoxy) and 4-hydroxy aromatic substituents, exhibited 96- and 335-fold greater selectivity for VMAT2 versus DAT and SERT, respectively, in comparison to lobelane. Thus, lobelane analogues bearing hydroxyl and fluoroethoxy moieties retain the high affinity for VMAT2 of the parent compound, while enhancing selectivity for VMAT2 versus the plasmalemma transporters.

Keywords: 4-Hydroxyphenyl lobelane analogues; Dopamine and serotonin transporter; Dopamine uptake; Fluorinated lobelane analogues; Vesicular monoamine transporter-2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemistry Techniques, Synthetic
  • Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopamine Uptake Inhibitors / chemistry*
  • Dopamine Uptake Inhibitors / pharmacology*
  • Drug Evaluation, Preclinical / methods
  • Lobeline / analogs & derivatives*
  • Lobeline / chemical synthesis
  • Lobeline / chemistry
  • Lobeline / pharmacology
  • Selective Serotonin Reuptake Inhibitors / chemistry
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Structure-Activity Relationship
  • Vesicular Monoamine Transport Proteins / antagonists & inhibitors
  • Vesicular Monoamine Transport Proteins / metabolism*

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine
  • SLC18A2 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Vesicular Monoamine Transport Proteins
  • lobelane
  • Lobeline