Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers

(S)-Aporphine metho salts with the 1,2,9,10 oxygenation pattern displaced radioligands from recombinant human α7 and α4β2 neuronal nicotinic acetylcholine receptors (nAChR) at low micromolar concentrations. The affinity of the nonphenolic glaucine methiodide (4) (vs [3H]cytisine) was the lowest at α4β2 nAChR (Ki = 10 μM), and predicentrine methiodide (2) and xanthoplanine iodide (3), with free hydroxyl groups at C-2 or C-9, respectively, had the highest affinity at these receptors (Ki ≈ 1 μM), while the affinity of the diphenolic boldine methiodide (1) was intermediate between these values. At homomeric α7 nAChR, xanthoplanine had the highest affinity (Ki = 10 μM) vs [125I]α-bungarotoxin while the other three compounds displaced the radioligand with Ki values between 15 and 21 μM. At 100 μM, all four compounds inhibited the responses of these receptors to EC50 concentrations of ACh. The effects of xanthoplanine iodide (3) were studied in more detail. Xanthoplanine fully inhibited the EC50 ACh responses of both α7 and α4β2 nACh receptors with estimated IC50 values of 9 ± 3 μM (α7) and 5 ± 0.8 μM (α4β2).

Several 1,2,9,10-tetraoxygenated aporphine metho salts were evaluated as α7 and α4β2 neuronal nicotinic acetylcholine receptor antagonists. Xanthoplanine, the most potent compound of the series, blocked both receptor subtypes at low micromolar concentrations.Figure optionsDownload as PowerPoint slide