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The acetylcholinesterase inhibitor BW284c51 is a potent blocker of Torpedo nicotinic AchRs incorporated into the Xenopus oocyte membrane
Author(s) -
OliveraBravo Silvia,
Ivorra Isabel,
Morales Andrés
Publication year - 2005
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705965
Subject(s) - nicotinic agonist , xenopus , chemistry , pharmacology , acetylcholine receptor , acetylcholinesterase , acetylcholine , tacrine , muscarinic acetylcholine receptor , nicotinic antagonist , biochemistry , biophysics , acetylcholinesterase inhibitor , receptor , biology , enzyme , gene
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