New tetrahydrobenzindoles as potent and selective 5-HT(7) antagonists with increased In vitro metabolic stability

Bioorg Med Chem Lett. 2003 Jan 6;13(1):61-4. doi: 10.1016/s0960-894x(02)00842-9.

Abstract

Chemical modifications of compound 1 (DR4004), a potent, selective antagonist of the 5-HT(7) receptor, were conducted with the aim of improving its metabolic stability. Halogenation of putative sites of oxidative metabolism afforded compounds 7-10, which retained high affinity and selectivity for the 5-HT(7) receptor, and showed increased in vitro metabolic stability. Compound 10 (DR4485) showed oral bioavailability, and should be a useful tool for evaluating the therapeutic potential of 5-HT(7) antagonists.

MeSH terms

  • Animals
  • Biological Availability
  • Cell Line
  • Cyclic AMP / metabolism
  • Drug Stability
  • Halogens
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacokinetics
  • Indoles / pharmacology
  • Pyridines
  • Radioligand Assay
  • Rats
  • Receptors, Serotonin / chemistry*
  • Receptors, Serotonin / drug effects
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / pharmacokinetics
  • Serotonin Antagonists / pharmacology
  • Structure-Activity Relationship

Substances

  • DR-4004
  • Halogens
  • Indoles
  • Pyridines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • serotonin 7 receptor
  • Cyclic AMP