Synthesis and SAR study of a novel series of dopamine receptor agonists

  • Bioorg Med Chem. 2014 Jan 1;22(1):381-92. doi: 10.1016/j.bmc.2013.11.012.
Rune Risgaard  1 ,  Martin Jensen  2 ,  Morten Jørgensen  2 ,  Benny Bang-Andersen  2 ,  Claus T Christoffersen  3 ,  Klaus G Jensen  3 ,  Jesper L Kristensen  4 ,  Ask Püschl  5
Affiliations
  • 1. Neuroscience Drug Discovery, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark; Department of Drug Design and Pharmacology, The Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
  • 2. Neuroscience Drug Discovery, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
  • 3. Drug ADME Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark.
  • 4. Department of Drug Design and Pharmacology, The Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
  • 5. Neuroscience Drug Discovery, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark. Electronic address: [email protected].
PMID: 24296012 DOI: 10.1016/j.bmc.2013.11.012
Abstract

The synthesis of a novel series of Dopamine Receptor agonists are described as well as their in vitro potency and efficacy on dopamine D₁ and D₂ receptors. This series was designed from pergolide and (4aR,10aR)-1-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinolin-6-ol (PHBQ) and resulted in the synthesis of (2R,4aR,10aR)-2-methylsulfanylmethyl-4-propyl-3,4,4a,5,10,10a-hexahydro-2H-naphtho[2,3-b][1,4]oxazin-9-ol (compound 27), which has a D₁ and D₂ receptor profile similar to that of the most recently approved drug for Parkinson's disease, rotigotine.

Keywords
Dopamine receptor agonist; Parkinson’s disease; Rotigotine.