BACKGROUND AND PURPOSE: Strong implications in major neurological diseases make the neuronal α4β2 nicotinic ACh receptor (nAChR) a highly interesting drug target. In this study, we present a detailed electrophysiological characterization of NS9283, a potent positive allosteric modulator acting selectively at 3α:2β stoichiometry of α2* and α4* nAChRs. EXPERIMENTAL APPROACH: The whole-cell patch-clamp technique equipped with an ultra-fast drug application system was used to perform electrophysiological characterization of NS9283 modulatory actions on human α4β2 nAChRs stably expressed in HEK293 cells (HEK293-hα4β2). KEY RESULTS: NS9283 was demonstrated to increase the potency of ACh-evoked currents in HEK293-hα4β2 cells by left-shifting the concentration-response curve ~60-fold. Interestingly, this modulation did not significantly alter maximal efficacy levels of ACh. Further, NS9283 did not affect the rate of desensitization of ACh-evoked currents, was incapable of reactivating desensitized receptors and only moderately slowed recovery from desensitization. However, NS9283 strongly decreased the rate of deactivation kinetics and also modestly decreased the rate of activation. This resulted in a left-shift of the ACh window current of (α4)3(β2)2 nAChRs in the presence of NS9283. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that NS9283 increases responsiveness of human (α4)3(β2)2 nAChR to ACh with no change in maximum efficacy. We propose that this potentiation is due to a significant slowing of deactivation kinetics. In summary, the mechanism of action of NS9283 bears high resemblance to that of benzodiazepines at the GABAA receptor and to our knowledge, NS9283 constitutes the first nAChR compound of this class.
BACKGROUND AND PURPOSE: Strong implications in major neurological diseases make the neuronal α4β2 nicotinic ACh receptor (nAChR) a highly interesting drug target. In this study, we present a detailed electrophysiological characterization of NS9283, a potent positive allosteric modulator acting selectively at 3α:2β stoichiometry of α2* and α4* nAChRs. EXPERIMENTAL APPROACH: The whole-cell patch-clamp technique equipped with an ultra-fast drug application system was used to perform electrophysiological characterization of NS9283 modulatory actions on human α4β2 nAChRs stably expressed in HEK293 cells (HEK293-hα4β2). KEY RESULTS:NS9283 was demonstrated to increase the potency of ACh-evoked currents in HEK293-hα4β2 cells by left-shifting the concentration-response curve ~60-fold. Interestingly, this modulation did not significantly alter maximal efficacy levels of ACh. Further, NS9283 did not affect the rate of desensitization of ACh-evoked currents, was incapable of reactivating desensitized receptors and only moderately slowed recovery from desensitization. However, NS9283 strongly decreased the rate of deactivation kinetics and also modestly decreased the rate of activation. This resulted in a left-shift of the ACh window current of (α4)3(β2)2 nAChRs in the presence of NS9283. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that NS9283 increases responsiveness of human (α4)3(β2)2 nAChR to ACh with no change in maximum efficacy. We propose that this potentiation is due to a significant slowing of deactivation kinetics. In summary, the mechanism of action of NS9283 bears high resemblance to that of benzodiazepines at the GABAA receptor and to our knowledge, NS9283 constitutes the first nAChR compound of this class.
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