Details

Autor(en) / Beteiligte

• Burstein, Ethan S.
• Carlsson, Maria L.
• Owens, Michelle
• Ma, Jian-Nong
• Schiffer, Hans H.
• Carlsson, Arvid
• Hacksell, Uli

Titel

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

Ist Teil von

• JOURNAL OF NEURAL TRANSMISSION, 2011-11, Vol.118 (11), p.1523-1533

Ort / Verlag

Vienna: Springer Vienna

Erscheinungsjahr

2011

Quelle

SpringerLink

Beschreibungen/Notizen

• (−)-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.