title: II. In vitro evidence that (-)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors.
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.
authors.affiliation: ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd., San Diego, CA 92121, USA. eburstein@acadia-pharm.com
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
authors.forename: Maria L
authors.initials: ML
authors.lastname: Carlsson
authors.forename: Michelle
authors.initials: M
authors.lastname: Owens
authors.forename: Jian-Nong
authors.initials: JN
authors.lastname: Ma
authors.forename: Hans H
authors.initials: HH
authors.lastname: Schiffer
authors.forename: Arvid
authors.initials: A
authors.lastname: Carlsson
authors.forename: Uli
authors.initials: U
authors.lastname: Hacksell
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D013347:Subcellular Fractions
chemical_list: D018491:Dopamine Agonists; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D058826:Serotonin 5-HT2 Receptor Agonists; C109513:OSU 6162