The acetylcholinesterase inhibitor BW284c51 is a potent blocker of Torpedo nicotinic AchRs incorporated into the Xenopus oocyte membrane

1 This work was aimed to determine if 1,5‐bis(4‐allyldimethylammoniumphenyl)pentan‐3‐one dibromide (BW284c51), the most selective acetylcholinesterase inhibitor (AchEI), affects the nicotinic acetylcholine (Ach) receptor (AchR) function. 2 Purified Torpedo nicotinic AchRs were injected into Xenopus laevis oocytes and BW284c51 effects on Ach‐ and carbamylcholine (Cch)‐elicited currents were assessed using the voltage‐clamp technique. 3 BW284c51 (up to 1 m M ) did not evoke any change in the oocyte membrane conductance. When BW284c51 (10 p M –100  μ M ) and Ach were coapplied, Ach‐evoked currents ( I Ach ) were reversibly inhibited in a concentration‐dependent manner (Hill coefficient, 1; IC 50 , 0.2–0.5  μ M for 0.1–1000  μ M Ach). Cch‐elicited currents showed a similar inhibition by BW284c51. 4 I Ach blockade by BW284c51 showed a strong voltage dependence, being only apparent at hyperpolarising potentials. BW284c51 also enhanced I Ach desensitisation. 5 BW284c51 changed the Ach concentration‐dependence curve of Torpedo AchR response from two‐site to single‐site kinetics, without noticeably affecting the EC 50 value. 6 The BW284c51 blocking effect was highly selective for nicotinic over muscarinic receptors. BW284c51 inhibition potency was stronger than that of tacrine, and similar to that of d ‐tubocurarine ( d ‐TC). Coapplication of BW284c51 with either tacrine or d ‐TC revealed synergistic inhibitory effects. 7 Our results indicate that BW284c51 antagonises nicotinic AchRs in a noncompetitive way by blocking the receptor channel, and possibly by other, yet unknown, mechanisms. 8 Therefore, besides acting as a selective AchEI, BW284c51 constitutes a powerful and reversible blocker of nicotinic AchRs that might be used as a valuable tool for understanding their function.British Journal of Pharmacology (2005) 144 , 88–97. doi: 10.1038/sj.bjp.0705965