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The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia

Author

Listed:
  • Linda J Bristow
  • Amy E Easton
  • Yu-Wen Li
  • Digavalli V Sivarao
  • Regina Lidge
  • Kelli M Jones
  • Debra Post-Munson
  • Christopher Daly
  • Nicholas J Lodge
  • Lizbeth Gallagher
  • Thaddeus Molski
  • Richard Pieschl
  • Ping Chen
  • Adam Hendricson
  • Ryan Westphal
  • James Cook
  • Christiana Iwuagwu
  • Daniel Morgan
  • Yulia Benitex
  • Dalton King
  • John E Macor
  • Robert Zaczek
  • Richard Olson

Abstract

The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8.1 nM) and agonist activity in a calcium fluorescence assay (EC50 = 23.4 nM) and whole cell voltage clamp electrophysiology (EC50 = 0.14 micromolar (rat) and 0.29 micromolar (human)). BMS-933043 exhibited a partial agonist profile relative to acetylcholine; the relative efficacy for net charge crossing the cell membrane was 67% and 78% at rat and human alpha7 nicotinic acetylcholine receptors respectively. BMS-933043 showed no agonist or antagonist activity at other nicotinic acetylcholine receptor subtypes and was at least 300 fold weaker at binding to and antagonizing human 5-HT3A receptors (Ki = 2,451 nM; IC50 = 8,066 nM). BMS-933043 treatment i) improved 24 hour novel object recognition memory in mice (0.1–10 mg/kg, sc), ii) reversed MK-801-induced deficits in Y maze performance in mice (1–10 mg/kg, sc) and set shift performance in rats (1–10 mg/kg, po) and iii) reduced the number of trials required to complete the extradimensional shift discrimination in neonatal PCP treated rats performing the intra-dimensional/extradimensional set shifting task (0.1–3 mg/kg, po). BMS-933043 also improved auditory gating (0.56–3 mg/kg, sc) and mismatch negativity (0.03–3 mg/kg, sc) in rats treated with S(+)ketamine or neonatal phencyclidine respectively. Given this favorable preclinical profile BMS-933043 was selected for further development to support clinical evaluation in humans.

Suggested Citation

  • Linda J Bristow & Amy E Easton & Yu-Wen Li & Digavalli V Sivarao & Regina Lidge & Kelli M Jones & Debra Post-Munson & Christopher Daly & Nicholas J Lodge & Lizbeth Gallagher & Thaddeus Molski & Richar, 2016. "The Novel, Nicotinic Alpha7 Receptor Partial Agonist, BMS-933043, Improves Cognition and Sensory Processing in Preclinical Models of Schizophrenia," PLOS ONE, Public Library of Science, vol. 11(7), pages 1-29, July.
  • Handle: RePEc:plo:pone00:0159996
    DOI: 10.1371/journal.pone.0159996
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    1. Tsang, Eric W. K., 2014. "Old and New," Management and Organization Review, Cambridge University Press, vol. 10(03), pages 390-390, November.
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