Modified ibogaine fragments: synthesis and preliminary pharmacological characterization of 3-ethyl-5-phenyl-1,2,3,4,5, 6-hexahydroazepino[4,5-b]benzothiophenes

J Med Chem. 1998 Nov 5;41(23):4486-91. doi: 10.1021/jm980156y.

Abstract

Five phenyl-substituted derivatives and analogues of 1,2,3,4,5, 6-hexahydroazepino[4,5-b]indole, 5, a major fragment of ibogaine (1), were synthesized and tested for binding to monoamine transporters, the NMDA receptor-coupled cation channel, and dopamine and opioid receptors. All five derivatives, 9 and 17a-d, displayed 8-10-fold higher affinity at the DA transporter than ibogaine and noribogaine (4). At the serotonin transporter, two compounds (9 and 17a) exhibited higher potency than ibogaine, while the rest had weaker binding affinities than the lead compound. In keeping with their structural similarity to ibogaine, all five compounds displayed weak to poor affinity for dopamine D1 and D2 receptors. However, two compounds, 17a,c, demonstrated moderate binding affinities at dopamine D3 receptors. All five compounds displayed weak to poor affinities for mu and kappa opioid receptors and for the NMDA receptor-coupled cation channel. Despite the qualitative differences, derivatives and analogues of 5may serve as useful substitutes for ibogaine.

MeSH terms

  • Animals
  • Brain / metabolism
  • Carrier Proteins / metabolism
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins
  • Excitatory Amino Acid Antagonists* / chemical synthesis
  • Excitatory Amino Acid Antagonists* / chemistry
  • Excitatory Amino Acid Antagonists* / pharmacology
  • Hallucinogens* / chemical synthesis
  • Hallucinogens* / chemistry
  • Hallucinogens* / pharmacology
  • Humans
  • Ibogaine* / chemistry
  • Ibogaine* / pharmacology
  • In Vitro Techniques
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins*
  • Nerve Tissue Proteins*
  • Radioligand Assay
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D3
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, Opioid, kappa / metabolism
  • Receptors, Opioid, mu / metabolism
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins
  • Thiophenes* / chemical synthesis
  • Thiophenes* / chemistry
  • Thiophenes* / pharmacology

Substances

  • Carrier Proteins
  • DRD3 protein, human
  • Dopamine Plasma Membrane Transport Proteins
  • Excitatory Amino Acid Antagonists
  • Hallucinogens
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Thiophenes
  • Serotonin
  • Ibogaine
  • Dopamine