II. In vitro evidence that (-)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors

J Neural Transm (Vienna). 2011 Nov;118(11):1523-33. doi: 10.1007/s00702-011-0701-y. Epub 2011 Aug 25.

Abstract

(-)-OSU6162 has promise for treating Parkinson's disease, Huntington's disease and schizophrenia. Behavioral tests evaluating the locomotor effects of (-) and (+)-OSU6162 on 'low activity' animals (reserpinized mice and habituated rats) and 'high activity' animals (drug naive mice and non-habituated rats) revealed that both enantiomers of OSU6162 had dual effects on behavior, stimulating locomotor activity in 'low activity' animals and inhibiting locomotor activity in 'high activity' animals. To elucidate a plausible mechanism of action for their behavioral effects, we evaluated the intrinsic actions of (-)- and (+)-OSU6162, and a collection of other antipsychotic and antiparkinsonian agents at 5-HT2A and D2 receptors in functional assays with various degrees of receptor reserve, including cellular proliferation, phosphatidyl inositol hydrolysis, GTPγS and beta-arrestin recruitment assays. We also tested for possible allosteric actions of (-)-OSU6162 at D2 receptors. Both enantiomers of OSU6162 were medium intrinsic activity partial agonists at 5-HT2A receptors and low intrinsic activity partial agonists at D2 receptors. (+)-OSU6162 had higher efficacy at 5-HT2A receptors, which correlated with its greater stimulatory activity in vivo, but (-)-OSU6162 had higher potency at D2 receptors, which correlated with its greater inhibitory activity in vivo. (-)-OSU6162 did not display any convincing allosteric properties. Both (+)- and (-)-OSU6162 were significantly less active at 27 other monoaminergic receptors and reuptake transporters tested suggesting that D2 and 5-HT2A receptors play crucial roles in mediating their behavioral effects. Compounds with balanced effects on these two receptor systems may offer promise for treating neuropsychiatric diseases.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Dopamine Agonists / pharmacology*
  • HEK293 Cells
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Receptor, Serotonin, 5-HT2A / physiology*
  • Receptors, Dopamine D2 / physiology*
  • Serotonin 5-HT2 Receptor Agonists / pharmacology*
  • Subcellular Fractions

Substances

  • Dopamine Agonists
  • Piperidines
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Serotonin 5-HT2 Receptor Agonists
  • OSU 6162