MODIFIED IBOGAINE FRAGMENTS - SYNTHESIS AND PRELIMINARY PHARMACOLOGICAL CHARACTERIZATION OF 1,2,3,4,5,6-HEXAHYDROAZEPINO[4,5-B]BENZOTHIOPHENES

Five phenyl-substituted derivatives and analogues of 1,2,3,4,5,6-hexah ydroazepino[4,5-b]indol 5, a major fragment of ibogaine (1), were synt hesized and tested for binding to monoamine transporters, the NMDA rec eptor-coupled cation channel, and dopamine and opioid receptors. All f ive derivatives, 9 and 17a-d, displayed 8-10-fold higher affinity at t he 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 c ompound. 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 bindin g affinities at dopamine D3 receptors. All five compounds displayed we ak to poor affinities for mu and kappa opioid receptors and for the NM DA receptor-coupled cation channel. Despite the qualitative difference s, derivatives and analogues of 5 may serve as useful substitutes for ibogaine.