Feuerbach, Dominik, Arias, Hugo R, De Rosa, Maria Jose and Bouzat, Cecilia (2013) Differential Pharmacological Activity of JN403 At α7 and Muscle Nicotinic Acetylcholine Receptors. The International Journal of Biochemistry & Cell Biology.

Abstract

The functional and structural interaction of the nicotinic acetylcholine receptor (AChR) α7 agonist JN403 was compared at human neuronal α7 and muscle-type nAChRs by using a combination of pharmacological, fluorescence, electrophysiological and computational approaches. Single-channel recordings established that JN403 is a potent agonist of α7 AChRs but a very low efficacy agonist of muscle AChRs. JN403 elicits detectable α7 AChR channel openings at concentrations >1,000-fold lower than that for ACh, whereas in muscle AChRs the concentration is about 50-fold higher than that for ACh. Opening events are brief and infrequent and do not appear in clusters at any concentration range. In addition, JN403 produces significant channel block of ACh-elicited openings. In agreement with its low-efficacious activity and potent blocking properties, JN403 binds with very low affinity to desensitized AChR agonist sites, does not elicit detectable Ca2+ influx in cells expressing embryonic and adult muscle AChRs but inhibits (±)-epibatidine-elicited influx, thus behaving functionally as an antagonist. The [3H]TCP binding experiments to locate the blocking site in the channel indicate that JN403 binds with very low affinity to this site in the desensitized AChR, suggesting that this domain is not the most important for the observed open-channel blockade. Patch-clamp results also suggest that JN403 induces AChR desensitization. This is supported by the radioligand binding results showing that JN403 enhances [3H]cytisine and [3H]TCP binding to AChRs in the resting state, probably by a desensitizing mechanism and apparent potency of ~30 µM. The observed high selectivity of JN403 for neuronal α7 AChRs might be important for the development of future therapies for the treatment of neurological diseases involving this AChR subtype.

Item Type:	Article
Date Deposited:	10 May 2016 23:45
Last Modified:	10 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/10067