Synthesis of new serotonin 5-HT7 receptor ligands. Determinants of 5-HT7/5-HT1A receptor selectivity

J Med Chem. 2009 Apr 23;52(8):2384-92. doi: 10.1021/jm8014553.

Abstract

We report the synthesis of a new set of compounds of general structure I (1-20) with structural modifications in the pharmacophoric elements of the previously reported lead UCM-5600. The new derivatives have been evaluated for binding affinity at 5-HT(7) and 5-HT(1A) receptors. The influence of the different structural features in terms of 5-HT(7)/5-HT(1A) receptor affinity and selectivity was analyzed by computational simulations of the complexes between compounds I and beta(2)-based 3-D models of these receptors. Compound 18 (HYD(1) = 1,3-dihydro-2H-indol-2-one; spacer = -(CH(2))(4)-; HYD(2) + HYD(3) = 3,4-dihydroisoquinolin-2(1H)-yl) exhibits high 5-HT(7)R affinity (K(i) = 7 nM) and selectivity over the 5-HT(1A)R (31-fold), and has been characterized as a partial agonist of the human 5-HT(7)R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Drug Partial Agonism
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Radioligand Assay
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptors, Serotonin / metabolism*
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / pharmacology
  • Structure-Activity Relationship

Substances

  • 1-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)-1,3-dihydro-2H-indol-2-one
  • Indoles
  • Isoquinolines
  • Ligands
  • Receptors, Serotonin
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • serotonin 7 receptor
  • Receptor, Serotonin, 5-HT1A