The development of an agonist for the a9a10 nicotinic cholinergic receptor

RACHEL E. REIFF; JUAN C. BOFFI; EDWIN G. PÉREZ; A. BELÉN ELGOYHEN

Huerta Grande, Córdoba

Congreso; Second Joint Meeting of the Argentine Society for Neuroscience (SAN) and the Argentine Workshop in Neurosciences (TAN). (IIRCN); 2010

The α9α10 nicotinic acetylcholine (ACh) receptor is expressed in outer hair cells ofthe organ of Corti, where it plays a crucial role in efferent modulation of soundamplification. With the exception of ACh, no effective agonists for this receptor areknown. In this study several structural ACh analogs were designed based onprevious investigations of molecular dynamics and tested as potential agonists forα9α10 using electrophysiology recordings in Xenopus oocytes. Four tertiaryammonium compounds elicited agonist‐induced responses, and two producedgreater responses than the maximal response of α9α10 to ACh. One particularlyeffective compound, 2‐((3‐methoxy‐3‐oxopropanoyl)oxy)‐N,N,Ntrimethylethanaminiumiodide, produced nearly 150% of the maximal response toACh (n=5). Compared with an EC50 of 15.35 ± 0.29 μM for ACh (n=7), this compoundhad an EC50 greater than 508.2 μM, and required a concentration of at least 129 μMto mimic the EC50 response of ACh. This compound was chosen as a lead compoundthat will be modified to improve selectivity and potency of the agonist. The iodidesof 2‐((4‐methoxy‐4‐oxobutanoyl)oxy)‐N,N,N‐trimethylethanaminium (n=3), 2‐((5‐methoxy‐5‐oxopentanoyl)oxy)‐N,N,N‐trimethylethanaminium (n=4), and 2‐(2‐methoxy‐2‐oxoacetoxy)‐N,N,N‐trimethylethanaminium (n=3) also acted as agonists,but were less potent than the lead compound. These results indicate a step towardthe development of a valuable drug to target α9α10.