Characterization of [3H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand

Claudia Rangel-Barajas, Maninder Malik, Michelle Taylor, Kim A. Neve, Robert H. Mach, Robert R. Luedtke

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

LS-3-134 is a substituted N-phenylpiperazine derivative that has been reported to exhibit: (i) high-affinity binding (Ki value 0.2 nM) at human D3 dopamine receptors, (ii) > 100-fold D3 versus D2 dopamine receptor subtype binding selectivity, and (iii) low-affinity binding (Ki > 5000 nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin-dependent activation of the adenylyl cyclase inhibition assay, LS-3-134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [3H]-labeled LS-3-134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10-15 min at 37C) and binds with high affinity to both human (Kd = 0.06 ± 0.01 nM) and rat (Kd = 0.2 ± 0.02 nM) D3 receptors expressed in HEK293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [3H]LS-3-134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies, we propose that [3H]LS-3-134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype.

Original languageEnglish (US)
Pages (from-to)418-431
Number of pages14
JournalJournal of Neurochemistry
Volume131
Issue number4
DOIs
StatePublished - Nov 1 2014

Keywords

  • D2-like dopamine receptors
  • D3 dopamine receptors
  • dopamine receptors
  • radioligand binding

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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