Synthesis and binding studies of 2-O- and 11-O-substituted N-alkylnoraporphines

Bioorg Med Chem Lett. 2008 Jul 15;18(14):3971-3. doi: 10.1016/j.bmcl.2008.06.016. Epub 2008 Jun 10.

Abstract

We synthesized several novel 2-O- or 11-O-substituted N-alkylnoraporphines and assessed their affinities at dopamine D(1) and D(2), and serotonin 5-HT(1A) receptors in rat forebrain tissue. Tested compounds displayed moderate to high affinities to D(2) receptors but low affinities to D(1) and 5HT(1A) receptors. The findings accord with previous evidence of a lipophilic cavity on the surface of the D(2) receptor to accommodate N-alkyl moieties of aporphines. The most D(2)-potent (K(i)=97 nM) and selective novel agent (>100-fold vs. D(1) and 5-HT(1A) sites) was R(-)-2-(2-hydroxyethoxy)-11-hydroxy-N-n-propylnoraporphine (compound 11).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aporphines / chemical synthesis*
  • Aporphines / chemistry
  • Chemistry, Pharmaceutical / methods
  • Drug Design
  • Kinetics
  • Models, Chemical
  • Prosencephalon / drug effects*
  • Prosencephalon / metabolism
  • Protein Binding
  • Rats
  • Receptor, Serotonin, 5-HT1A / chemistry
  • Receptors, Dopamine D1 / chemistry
  • Receptors, Dopamine D2 / chemistry
  • Receptors, Dopamine D2 / metabolism

Substances

  • Aporphines
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptor, Serotonin, 5-HT1A
  • aporphine
  • 11-hydroxy-N-(n-propyl)noraporphine