Modified Ibogaine Fragments:  Synthesis and Preliminary Pharmacological Characterization of 3-Ethyl-5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]benzothiophenes

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.

Synthesis and reactivity of thieno[2,3‐b]quinoline derivatives (Part II)

“…Efange, S. M. N. and colleagues reported the chloromethylation of benzo[ b ]thiophene 104a with formaldehyde and HCl to form the 3‐(chloromethyl)benzo[ b ]thiophene 133 , which upon treatment with potassium cyanide furnished the desired nitrile 130a (Scheme 32) [66]. Similarly, nucleophilic substitution reaction of 133 with sodium benzenesulfinate gave the sulfone 130b (Scheme 32) [67].…”

Phenylpiperazinylmethylheterocycle Derivatives: Synthesis and Dopamine Receptor Binding Profiles

“…Phenylpiperazinylmethylimidazo[1,2-a]pyridine 3Ϫ9 and phenylpiperazinylmethylpyrrole 10Ϫ16 derivatives were synthesized from the reaction of imidazo[1,2-a]pyridine [9] and pyrrole, respectively, with formaldehyde and the appropriate phenylpiperazine (Schemes 1 and 2). The reaction of benzofuran and benzothiophene with formaldehyde in the presence of concentrated HCl and bubbling HCl gas in the solution at low temperature resulted in the 3-chloromethyl derivatives [10,11]. The desired compounds 17Ϫ30 were obtained by reacting the 3-chloromethyl derivatives with the appropriate phenylpiperazine in the presence of triethylamine (Scheme 3).…”

Synthesis of [1]Benzothieno[2,3-b]quinolines via Transition-Metal-Free [3+3] Annulation of Nitroarenes and Benzo[b]thiophen-3-ylacetonitrile or 3-(Phenylsulfonylmethyl)benzo[b]thiophene Carbanions

“…The starting carbanion precursors nitrile 3a and sulfone 3b were readily obtained from commercially available benzo[b]thiophene (thionaphthene, 1) in two simple steps (Scheme 3). Chloromethylation of benzo[b]thiophene (1) with formaldehyde and HCl provided 3-(chloromethyl)benzo[b]thiophene (2), 12 which upon treatment with potassium cyanide furnished the desired nitrile 3a. 12 Analogously, the reaction of 2 with sodium benzenesulfinate provided the sulfone 3b.…”

“…Chloromethylation of benzo[b]thiophene (1) with formaldehyde and HCl provided 3-(chloromethyl)benzo[b]thiophene (2), 12 which upon treatment with potassium cyanide furnished the desired nitrile 3a. 12 Analogously, the reaction of 2 with sodium benzenesulfinate provided the sulfone 3b.…”

“…): m/z (%) = 412(8), 411 (34), 410 (19), 409 (67), 347(6), 346(12), 345 (16), 344 (26), 312(10), 311 (36), 310 (100), 309 (23), 286(9), 285 (14), 284 (21), 270(12), 269 (15), 268 (29), 267(6), 258(7), 256 (19), 234(12), 233 (62), 232(7), 226 (6), 224 (20), 206 (5), 189 (10), 188 (15), 155 (8), 77 (12). HRMS (EI): m/z calcd for C 21 (MeCN): λ max (ε) = 191 (18735), 215 (10327), 281 (11311), 318 (3274), 409 (3744).2-Bromo-11-(phenylsulfonyl)[1]benzothieno[2,3-b]quinoline (5bc)Column chromatography (silica gel, toluene-hexane, 1:1).Yellow solid; yield: 285 mg (66%); mp >250 °C (EtOAc).…”