Pharmacological characterization of the novel and selective α7 nicotinic acetylcholine receptor positive allosteric modulator BNC375

Wang, X. et al. (2020) Pharmacological characterization of the novel and selective α7 nicotinic acetylcholine receptor positive allosteric modulator BNC375. Journal of Pharmacology and Experimental Therapeutics, 373(2), pp. 311-324. (doi: 10.1124/jpet.119.263483) (PMID:32094294)

Abstract

Treatments for cognitive deficits associated with CNS disorders such as Alzheimer's disease (AD) and schizophrenia remain significant unmet medical needs that incur substantial pressure on the healthcare system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine (ACh)-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation (LTP) of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nAChR PAM that potentiates ACh-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in CNS diseases with cognitive impairments.

• Item Type: Articles
• Additional Information: This work was funded by Merck & Co., Inc. and Bionomics Limited.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Thomson, Dr Fiona
• Authors: Wang, X., Daley, C., Gakhar, V., Lange, H., Vardigan, J. D., Pearson, M., Zhou, X., Warren, L., Miller, C. O., Belden, M., Harvey, A. J., Grishin, A. A., Coles, C. J., O’Connor, S. M., Thomson, F., Duffy, J. L., Bell, I. M., and Uslaner, J. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Pharmacology and Experimental Therapeutics
• Publisher: American Society for Pharmacology and Experimental Therapeutics
• ISSN: 0022-3565
• ISSN (Online): 1521-0103
• Published Online: 24 February 2020