2. Academic Validation
  3. BNC210, a negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor, demonstrates anxiolytic- and antidepressant-like effects in rodents

BNC210, a negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor, demonstrates anxiolytic- and antidepressant-like effects in rodents

  • Neuropharmacology. 2024 Mar 15:246:109836. doi: 10.1016/j.neuropharm.2024.109836.
Susan M O'Connor 1,  Brad E Sleebs 2,  Ian P Street 3,  Bernard L Flynn 4,  Jonathan B Baell 5,  Carolyn Coles 6,  Nurul Quazi 7,  Dharam Paul 6,  Etienne Poiraud 8,  Bertrand Huyard 8,  Stephanie Wagner 8,  Emile Andriambeloson 8,  Errol B de Souza 6
Affiliations

Affiliations

  • 1 Bionomics Limited, Adelaide, Australia. Electronic address: sue.oconnor@abcellera.com.
  • 2 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • 3 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia; Children's Cancer Institute, School of Medicine and Health, UNSW, Randwick, Australia.
  • 4 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Melbourne, Australia.
  • 5 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Melbourne, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia.
  • 6 Bionomics Limited, Adelaide, Australia.
  • 7 The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia.
  • 8 Neurofit, Illkirch-Graffenstaden, France.
PMID: 38185416 DOI: 10.1016/j.neuropharm.2024.109836
Abstract

This work describes the characterization of BNC210 (6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(4-morpholinylcarbonyl)-1,8-naphthyridin-4(1H)-one), a selective, small molecule, negative allosteric modulator (NAM) of α7 nicotinic acetylcholine receptors (α7 nAChR). With the aim to discover a non-sedating, anxiolytic compound, BNC210 was identified during phenotypic screening of a focused medicinal chemistry library using the mouse LIGHT Dark (LD) box to evaluate anxiolytic-like activity and the mouse Open Field (OF) (dark) test to detect sedative and/or motor effects. BNC210 exhibited anxiolytic-like activity with no measurable sedative or motor effects. Electrophysiology showed that BNC210 did not induce α7 nAChR currents by itself but inhibited EC80 agonist-evoked currents in recombinant GH4C1 cell lines stably expressing the rat or human α7 nAChR. BNC210 was not active when tested on cell lines expressing other members of the cys-loop ligand-gated ion channel family. Screening over 400 other targets did not reveal any activity for BNC210 confirming its selectivity for α7 nAChR. Oral administration of BNC210 to male mice and rats in several tests of behavior related to anxiety- and stress- related disorders, demonstrated significant reduction of these behaviors over a broad therapeutic range up to 500 times the minimum effective dose. Further testing for potential adverse effects in suitable rat and mouse tests showed that BNC210 did not produce sedation, memory and motor impairment or physical dependence, symptoms associated with current anxiolytic therapeutics. These data suggest that allosteric inhibition of α7 nAChR function may represent a differentiated approach to treating anxiety- and stress- related disorders with an improved safety profile compared to current treatments.

Keywords

Alpha 7 nicotinic acetylcholine receptor; Anxiety and stress-related disorders; Depression; Fear extinction; Negative allosteric modulation.

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