Nicotinic acetylcholine receptors (nAChRs) are transmembrane proteins that mediate rapid synaptic transmission and belong to the superfamily of ligand-gated ion channels.Seventeen nAChRs subunits have been identified in vertebrate species, the last nAChR subunits that have been cloned are α9 and α10. These subunits assemble to form, inter alia, the α9α10 nAChR subtype which plays an important role in the central nervous system’s modulation of sound detection and amplification. To the best of our knowledge, with the exception of acetylcholine (ACh), no effective full agonists, natural or synthetic, are known to exist for the α9α10 nAChR. Here we describe the design, synthesis and pharmacological properties of ACh analogs that are the first synthetic full agonists for the α9α10 nAChR subtype. A series of new ACh analogs were synthesized, characterized and assayed at 300 μM on Xenopus oocytes expressing the α9α10 nAChR subtype. Based on their electrophysiological responses, five compounds (17a, 17d, 17e and 17f, Figure 1A) were selected for further study. Concentration-response curves for these five compounds were created (Figure 1B). The EC50, the maximal evoked response and Hill coefficients derived from these concentration-response curves are summarized in Table 1. In this study were discovered synthetic full agonists for the rat recombinant α9α10 receptor. Among these compounds, 17f, bearing an octyl group on the ammonium nitrogen, was determined to be the most potent one. These results are a promising step toward the development of pharmaceutical agents targeting the α9α10 receptor.

Design and synthesis of new acetylcholine analogues acting as full agonists for the nicotinic acetylcholine receptor subtype α9α10

252nd National Meeting (2016)

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