Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers

Abstract

(S)-Aporphine metho salts with the 1,2,9, 10 oxygenation pattern displaced radioligands from recombinant human 0 and alpha 4 beta 2 neuronal nicotinic acetylcholine receptors (nAChR) at low micromolar concentrations. The affinity of the nonphenolic glaucine methiodide (4) (vs [(3) H]cytisine) was the lowest at alpha 4 beta 2 nAChR (K-i = 10 mu M), 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 (K-i approximate to 1 mu M), while the affinity of the diphenolic boldine methiodide (1) was intermediate between these values. At homomeric alpha 7 nAChR, xanthoplanine had the highest affinity (K-i = 10 mu M) vs [(1251)]alpha-bungarotoxin while the other three compounds displaced the radioligand with K-i values between 15 and 21 mu M. At 100 mu M. 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 alpha 7 and alpha 4 beta 2 nACh receptors with estimated IC50 values of 9 +/- 3 mu M (alpha 7) and 5 +/- 0.8 mu M (alpha 4 beta 2). (c) 2007 Elsevier Ltd. All rights reserved.