N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist

Bioorg Med Chem Lett. 2003 Dec 15;13(24):4497-9. doi: 10.1016/j.bmcl.2003.08.038.


The identification of potent and selective orexin-2 receptor (OX(2)R) antagonists is described based on the modification of N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogue 1, recently discovered during high throughput screening (HTS). Substitution of an acyl group in 1 with tert-Leucine (tert-Leu), and introduction of a 4-pyridylmethyl substituent onto the amino function of tert-Leu improved compound potency, selectivity, and water solubility. Thus, compound 29 is a promising tool to investigate the role of orexin-2 receptors.

MeSH terms

  • Humans
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines / chemical synthesis*
  • Tetrahydroisoquinolines / chemistry
  • Tetrahydroisoquinolines / pharmacology*


  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Tetrahydroisoquinolines