Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT(2C) receptor agonists

Bioorg Med Chem Lett. 2006 Mar 1;16(5):1207-11. doi: 10.1016/j.bmcl.2005.11.083. Epub 2005 Dec 19.

Abstract

Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3', 2':4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Humans
  • Hydroxylation
  • Molecular Structure
  • Phospholipids / pharmacology
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry*
  • Pyrazines / pharmacology*
  • Pyrroles / chemistry*
  • Receptor, Serotonin, 5-HT2C / genetics
  • Receptor, Serotonin, 5-HT2C / metabolism
  • Serotonin 5-HT2 Receptor Agonists*
  • Structure-Activity Relationship

Substances

  • Phospholipids
  • Pyrazines
  • Pyrroles
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists