Synthesis and pharmacological evaluation of dual ligands for melatonin (MT1/MT2) and serotonin 5-HT2C receptor subtypes (II)

Eur J Med Chem. 2015 Jan 27:90:822-33. doi: 10.1016/j.ejmech.2014.12.021. Epub 2014 Dec 13.

Abstract

In this paper we report the investigation of C-3 and β-acetamide positions of agomelatine analogues. Concomitant insertion of a hydroxymethyl in the β-acetamide position and aliphatic groups in C-3 position produced a positive effect on both melatonin (MT1, MT2) and serotonin (5-HT2C) binding affinities. In particular, the allyl 6b and ethyl 15a represented the more interesting compounds of this series. Furthermore, the introduction of methyl cycloalkyl groups (compounds 11a, 12a) exhibited no change in both MT2 and 5-HT2C binding affinities while a decrease of MT1 binding affinity occurred leading to an MT2 selectivity. Finally, the acetamide modulation has led to methyl thiourea 11h, with a weak MT2 selectivity.

Keywords: Agomelatine; MT(2)-Selectivity; Melatonin receptors; Modulation; Serotonin 5-HT(2C) receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Animals
  • CHO Cells
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Structure
  • Receptor, Melatonin, MT1 / antagonists & inhibitors*
  • Receptor, Melatonin, MT1 / metabolism
  • Receptor, Melatonin, MT2 / antagonists & inhibitors*
  • Receptor, Melatonin, MT2 / metabolism
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Ligands
  • Receptor, Melatonin, MT1
  • Receptor, Melatonin, MT2
  • Receptor, Serotonin, 5-HT2C
  • agomelatine