Novel 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines as 5-HT6 agonists and antagonists

Bioorg Med Chem. 2007 Sep 15;15(18):6208-26. doi: 10.1016/j.bmc.2007.06.024. Epub 2007 Jun 14.

Abstract

1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists.

MeSH terms

  • Binding, Competitive
  • HeLa Cells / drug effects
  • Humans
  • Ligands
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptors, Serotonin / chemistry*
  • Receptors, Serotonin / metabolism
  • 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

  • Ligands
  • Pyridines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • serotonin 6 receptor