Oral r‐(‐)‐11‐o‐valeryl‐n‐n‐propylnoraporphine reverses motor deficits in mptp‐treated marmosets. Issue 9 (2nd May 2016)

• Record Type: Journal Article
• Authors: Lincoln, Louise; Fisher, Ria; Jackson, Michael J.; Jenner, Peter; Neumeyer, John; Sromek, Anna W.; Lees, Andrew J.; Rose, Sarah
• Other Names: Sánchez‐Ferro Álvaro guestEditor.; Maetzler Walter guestEditor.
• Is Part Of: Movement disorders. Volume 31:Issue 9(2016)
• Page Start: 1381
• Page End: 1388
• Publication Date: 2016-05-02
• Subjects: 11‐OH‐NPa valerate -- apomorphine -- marmosets -- MPTP -- Parkinson's disease -- R‐(‐)‐11‐O‐valeryl‐N‐n‐propylnoraporphine; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.26626
• Languages: English
• ISSNs: 0885-3185

Abstract

ABSTRACT: Background: 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. Methods: 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). Results: 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. Conclusion: 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