2-[N-Acylamino(C1-C3)alkyl]indoles as MT1 melatonin receptor partial agonists, antagonists, and putative inverse agonists

J Med Chem. 1998 Sep 10;41(19):3624-34. doi: 10.1021/jm970721h.

Abstract

The synthesis of several novel indole melatonin analogues substituted at the 2-position with acylaminomethyl (8-11), acylaminoethyl (5a-k), or acylaminopropyl (13) side chains is reported. On the basis of a novel in vitro functional assay (specific binding of [35S]GTPgammaS), which can discriminate agonist from partial agonist, antagonist, and inverse agonist ligands, 5a,g, h,j and 13 were shown to be partial agonists, 5d,e and 8-11 competitive antagonists, and 5b,c,k putative inverse agonists. Binding and functional assays were performed on cloned human MT1 receptor. Structure-activity relationship considerations indicate that N-[1-aryl-2-(4-methoxy-1H-indol-2-yl)(C1-C2)alkyl]alkanamides represent a lead structure for this type of ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • GTP-Binding Proteins / metabolism
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology
  • Ligands
  • Melatonin / metabolism*
  • Mice
  • Rats
  • Receptors, Cell Surface / agonists*
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / biosynthesis
  • Receptors, Cell Surface / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / biosynthesis
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Melatonin
  • Sodium Chloride / metabolism
  • Structure-Activity Relationship

Substances

  • Indoles
  • Ligands
  • Receptors, Cell Surface
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Melatonin
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Sodium Chloride
  • GTP-Binding Proteins
  • Melatonin