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

Five new compounds derived from a fragment of ibogaine were synthesized and tested for their ability to bind to brain receptors and transporters. All five showed 8 to 10 times stronger binding to the dopamine transporter than ibogaine itself. Two compounds were more potent than ibogaine at the serotonin transporter, while the others were weaker. The compounds generally had weak binding to dopamine D1 and D2 receptors, but two showed moderate binding to dopamine D3 receptors. All had weak binding to opioid receptors and NMDA receptors. These derivatives may serve as useful substitutes for ibogaine in addiction therapy.

Study at a glance

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.