title: Oral r-(-)-11-o-valeryl-n-n-propylnoraporphine reverses motor deficits in mptp-treated marmosets.
abstract: The D1/D2 dopamine agonist apomorphine has poor oral bioavailability, necessitating subcutaneous administration in the treatment of Parkinson's disease (PD). Acute subcutaneous injection is used as rescue therapy from "off" periods, whereas continuous subcutaneous infusion is used to increase "on" periods and to reduce dyskinesia when oral treatment fails. An orally active derivative of apomorphine would avoid the need for parenteral administration. We now describe the effects of the orally active compound R-(-)-11-O-valeryl-N-n-propylnoraporphine (11-OH-NPa valerate) on reversal of motor disability and expression of dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, l-dopa-primed dyskinetic common marmosets.
  
  
  
  Locomotor activity, motor disability, and dyskinesia were assessed in MPTP-treated marmosets following the administration of apomorphine (0.075 mg/kg, subcutaneous and 0.28 to 1.12 mg/kg, oral) and 11-OH-NPa valerate (0.19, 0.38, and 0.75mg/kg, oral).
  
  
  
  Subcutaneous administration of apomorphine (0.075 mg/kg) produced a short-lasting reversal of motor disability and the expression of established dyskinesia, but when administered orally (0.28-1.12 mg/kg) it had no effect. In contrast, oral treatment with 11-OH-NPa valerate (0.19 and 0.75 mg/kg) induced a dose-related reversal of motor disability and increased locomotor activity with only mild to moderate dyskinesia. Only at the highest dose (0.75 mg/kg) was marked dyskinesia seen accompanying an extended period of motor disability reversal and increased locomotor activity.
  
  
  
  Oral administration of 11-OH-NPa valerate produced a rapid reversal of motor disability and, at effective dose levels, had a limited propensity to induce dyskinesia. 11-OH-NPa valerate is the first orally active derivative of apomorphine with potential for use in PD. © 2016 International Parkinson and Movement Disorder Society.
authors.affiliation: Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, Hodgkin Building, King's College London, London, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Lincoln
authors.affiliation: Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, Hodgkin Building, King's College London, London, UK.
authors.forename: Ria
authors.initials: R
authors.lastname: Fisher
authors.affiliation: Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, Hodgkin Building, King's College London, London, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jackson
authors.affiliation: Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, Hodgkin Building, King's College London, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Jenner
authors.affiliation: Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA.
authors.forename: John
authors.initials: J
authors.lastname: Neumeyer
authors.affiliation: Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA.
authors.forename: Anna W
authors.initials: AW
authors.lastname: Sromek
authors.affiliation: Reta Lila Weston Institute, University College London, London, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
authors.affiliation: Neurodegenerative Diseases Research Group, Faculty of Life Science and Medicine, Hodgkin Building, King's College London, London, UK. sarah.rose@kcl.ac.uk.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rose
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000008:administration & dosage / Q000494:pharmacology*; D001060:Aporphines / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002144:Callithrix; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D020267:MPTP Poisoning / Q000188:drug therapy*; D008297:Male; D014631:Valerates / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D001060:Aporphines; D018491:Dopamine Agonists; D014631:Valerates; C008081:11-hydroxy-N-(n-propyl)noraporphine; D001058:Apomorphine
keywords: 11-OH-NPa valerate; MPTP; Parkinson's disease; R-(-)-11-O-valeryl-N-n-propylnoraporphine; apomorphine; marmosets