Novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines as potent and selective agonists of the 5-HT2C receptor

Bioorg Med Chem Lett. 2021 Apr 15:38:127872. doi: 10.1016/j.bmcl.2021.127872. Epub 2021 Feb 23.

Abstract

A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.

Keywords: 5-HT(2C) agonists; CNS drugs; Lorcaserin; Naphthyridine; Tricyclic amines.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Rats
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / chemical synthesis
  • Serotonin 5-HT2 Receptor Agonists / chemistry
  • Serotonin 5-HT2 Receptor Agonists / pharmacology*
  • Structure-Activity Relationship

Substances

  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists