Planta Med 2012; 78 - CL20
DOI: 10.1055/s-0032-1320255

Natural product derivative that cross the blood brain barrier (BBB) and protect dopamine neurons in Parkinson disease (PD) models

G Le Douaron 1, 2, F Schmidt 1, 2, M Amar 1, 2, H Kadar 3, B Séon-Méniel 1, L Ferrié 1, D Touboul 3, A Brunelle 3, R Raisman-Vozari 2, B Figadère 1
  • 1CNRS-UMR 8076 BiOCIS, Université Paris-Sud, 92296 Châtenay-Malabry Cedex, France
  • 2INSERM UMR 975– CNRS UMR 7225– CRICM, CHU Pitié-Salpêtrière, 75013 Paris, France
  • 3Institut de Chimie des Substances Naturelles, CNRS UPR 2301, 91198, Gif-Sur-Yvette, France

Recently our laboratory synthesized hybrids of natural products (melatonin and fatty acid) with the aim to develop drugs possessing dual properties, namely neuroprotective and neuritogenic. Through a cell-based screening on PD model of the thus synthesized focused chemical library, we found compounds exhibiting both activities. (Bioorg. Med. Chem. 2010, p.5103). The development of the lead compound brings in light its weak ability to cross the BBB. In order to increase this ability, we synthesized 2nd generation compounds, derived from amino-quinoxalines. Their synthesis would be discussed. After screening these molecules in the in vitro PD model, we were able to identify a compound, which exhibited both neuroprotective activity and good physico-chemical properties that allows a good BBB permeation in regards to QSARs study. HPLC/MS-MS analysis and MALDI-TOF imaging of brain treated mice tissues (per. os. 150mg/kg) reach to confirmation of the QSARs prediction. Then PD MPP+ lesioned mice model was used to evaluate the in vivo activity of our lead compound. Finally, a 3rd generation library was synthesized and screened. Our most recent results will be presented.