Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: I. neurochemical characterisation of RG-15

Naunyn Schmiedebergs Arch Pharmacol. 2008 Nov;378(5):515-28. doi: 10.1007/s00210-008-0308-5. Epub 2008 Jun 13.


RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl]-cyclohexyl]-3-pyridinesulfonic amide dihydrochloride) displayed subnanomolar affinity to human and rat dopamine D3 receptors (pKi 10.49 and 9.42, respectively) and nanomolar affinity to human and rat D2 receptors (pKi 8.23 and 7.62, respectively). No apparent interactions were found with the other 44 receptors and four channel sites tested in this study. RG-15 inhibited dopamine-stimulated [35S]GTPgammaS binding in membranes from rat striatum, in murine A9 cells expressing human D2L receptors and in CHO cells expressing human D3 receptors (IC50 values were 21.2, 36.7 and 7.2 nM, respectively). In these tests RG-15 showed the highest affinity toward D3 receptors when compared to amisulpride, haloperidol and SB-277011. RG-15, similar to haloperidol and amisulpride, dose-dependently inhibited in vivo [3H]raclopride binding in mouse striatum, enhanced dopamine turnover and synthesis rate in mouse and rat striatum and olfactory tubercle. SB-277011 did not change [3H]raclopride binding in mouse striatum nor biosynthesis or turnover rates in either region in mice or rats. RG-15 and haloperidol, but not SB-277011, antagonised dopamine synthesis inhibition induced by the D3/D2 full agonist 7-OH-DPAT in GBL-treated mice. RG-15, but not SB-277011, elevated plasma prolactin levels. In vitro receptor binding and functional experiments demonstrated that RG-15 had an antagonist profile on both D3 and D2 receptors. with high selectivity for dopamine D3 receptors over D2 receptors. However, in vivo, its neurochemical actions were similar to those of D2 receptor antagonists. Neurochemical comparison of RG-15 with antagonists having a different affinity and selectivity toward D3 and D2 receptors indicate that D3 receptors have little, if any, role in the control of presynaptic dopamine biosynthesis/release in dopaminergic terminal regions.

Publication types

  • Comparative Study

MeSH terms

  • Amisulpride
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dopamine / metabolism
  • Dopamine Antagonists / administration & dosage
  • Dopamine Antagonists / pharmacology*
  • Dopamine D2 Receptor Antagonists*
  • Dose-Response Relationship, Drug
  • Haloperidol / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Nitriles / pharmacology
  • Prolactin / blood
  • Prolactin / drug effects
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology*
  • Sulpiride / analogs & derivatives
  • Sulpiride / pharmacology
  • Tetrahydroisoquinolines / pharmacology


  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • N-(4-(2-(4-(3-cyano-5-trifluoromethylphenyl)piperazin-1-yl)ethyl)cyclohexyl)-3-pyridinesulfonic amide
  • Nitriles
  • Pyridines
  • Receptors, Dopamine D3
  • SB 277011
  • Sulfonamides
  • Tetrahydroisoquinolines
  • Sulpiride
  • Amisulpride
  • Prolactin
  • Haloperidol
  • Dopamine