Novel N-1,2-dihydroxypropyl analogs of lobelane inhibit vesicular monoamine transporter-2 function and methamphetamine-evoked dopamine release

J Pharmacol Exp Ther. 2011 Oct;339(1):286-97. doi: 10.1124/jpet.111.184770. Epub 2011 Jul 21.

Abstract

Lobelane, a chemically defunctionalized saturated analog of lobeline, has increased selectivity for the vesicular monoamine transporter 2 (VMAT2) compared with the parent compound. Lobelane inhibits methamphetamine-evoked dopamine (DA) release and decreases methamphetamine self-administration. Unfortunately, tolerance develops to the ability of lobelane to decrease these behavioral effects of methamphetamine. Lobelane has low water solubility, which is problematic for drug development. The aim of the current study was to determine the pharmacological effect of replacement of the N-methyl moiety with a chiral N-1,2-dihydroxypropyl (N-1,2-diol) moiety, which enhances water solubility, altering the configuration of the N-1,2-diol moiety and incorporating phenyl ring substituents into the analogs. To determine VMAT2 selectivity, structure-activity relationships also were generated for inhibition of DA and serotonin transporters. Analogs with the highest potency for inhibiting DA uptake at VMAT2 and at least 10-fold selectivity were evaluated further for ability to inhibit methamphetamine-evoked DA release from superfused striatal slices. (R)-3-[2,6-cis-di(4-methoxyphenethyl)piperidin-1-yl]propane-1,2-diol (GZ-793A), the (R)-4-methoxyphenyl-N-1,2-diol analog, and (R)-3-[2,6-cis-di(1-naphthylethyl)piperidin-1-yl]propane-1,2-diol (GZ-794A), the (R)-1-naphthyl-N-1,2-diol analog, exhibited the highest potency (K(i) ∼30 nM) inhibiting VMAT2, and both analogs inhibited methamphetamine-evoked endogenous DA release (IC(50) = 10.6 and 0.4 μM, respectively). Thus, the pharmacophore for VMAT2 inhibition accommodates the N-1,2-diol moiety, which improves drug-likeness and enhances the potential for the development of these clinical candidates as treatments for methamphetamine abuse.

Publication types

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

MeSH terms

  • Amphetamine-Related Disorders / drug therapy
  • Animals
  • Binding, Competitive / drug effects
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Data Interpretation, Statistical
  • Dopamine / metabolism*
  • Dopamine Uptake Inhibitors / pharmacology*
  • Kinetics
  • Lobeline / analogs & derivatives*
  • Lobeline / chemical synthesis
  • Lobeline / pharmacology*
  • Male
  • Methamphetamine / pharmacology*
  • Nicotinic Agonists / chemical synthesis
  • Nicotinic Agonists / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Structure-Activity Relationship
  • Synaptic Vesicles / drug effects
  • Synaptic Vesicles / metabolism
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism
  • Vesicular Monoamine Transport Proteins / antagonists & inhibitors*
  • Vesicular Monoamine Transport Proteins / metabolism

Substances

  • Dopamine Uptake Inhibitors
  • N-(1,2-dihydroxylpropyl)-2,6-di-(4-methoxyphenethyl)piperidine
  • Nicotinic Agonists
  • Serotonin Plasma Membrane Transport Proteins
  • Slc18a2 protein, rat
  • Vesicular Monoamine Transport Proteins
  • Serotonin
  • Methamphetamine
  • Lobeline
  • Dopamine