Nicotinic alpha 7 receptor agonists EVP-6124 and BMS-933043, attenuate scopolamine-induced deficits in visuo-spatial paired associates learning

PLoS One. 2017 Dec 19;12(12):e0187609. doi: 10.1371/journal.pone.0187609. eCollection 2017.

Abstract

Agonists at the nicotinic acetylcholine alpha 7 receptor (nAChR α7) subtype have the potential to treat cognitive deficits in patients with Alzheimer's disease (AD) or schizophrenia. Visuo-spatial paired associates learning (vsPAL) is a task that has been shown to reliably predict conversion from mild cognitive impairment to AD in humans and can also be performed by nonhuman primates. Reversal of scopolamine-induced impairment of vsPAL performance may represent a translational approach for the development of nAChR α7 agonists. The present study investigated the effect of treatment with the acetylcholinesterase inhibitor, donepezil, or three nAChR α7 agonists, BMS-933043, EVP-6124 and RG3487, on vsPAL performance in scopolamine-treated cynomolgus monkeys. Scopolamine administration impaired vsPAL performance accuracy in a dose- and difficulty- dependent manner. The impairment of eventual accuracy, a measure of visuo-spatial learning during the task, was significantly ameliorated by treatment with donepezil (0.3 mg/kg, i.m.), EVP-6124 (0.01 mg/kg, i.m.) or BMS-933043 (0.03, 0.1 and 0.3 mg/kg, i.m.). Both nAChR α7 agonists showed inverted-U shaped dose-effect relationships with EVP-6124 effective at a single dose only whereas BMS-933043 was effective across at least a 10 fold dose/exposure range. RG3487 was not efficacious in this paradigm at the dose range examined (0.03-1 mg/kg, i.m.). These results are the first demonstration that the nAChR α7 agonists, EVP-6124 and BMS-933043, can ameliorate scopolamine-induced cognitive deficits in nonhuman primates performing the vsPAL task.

MeSH terms

  • Animals
  • Donepezil
  • Indans / pharmacology
  • Macaca fascicularis
  • Male
  • Paired-Associate Learning / drug effects*
  • Piperidines / pharmacology
  • Quinuclidines / chemistry
  • Quinuclidines / pharmacology*
  • Reaction Time / drug effects
  • Scopolamine
  • Space Perception / classification*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Task Performance and Analysis
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Treatment Outcome
  • Visual Perception / drug effects*
  • alpha7 Nicotinic Acetylcholine Receptor / agonists*

Substances

  • 7-chloro-N-quinuclidin-3-yl-benzo(b)thiophene-2-carboxamide
  • BMS-933043
  • Indans
  • Piperidines
  • Quinuclidines
  • Spiro Compounds
  • Thiophenes
  • alpha7 Nicotinic Acetylcholine Receptor
  • Donepezil
  • Scopolamine

Grants and funding

This work was funded in full by BMS, and all authors were BMS employees during their contribution to this project. Some authors own stock in BMS. BMS only provided financial support in the form of authors' salaries and/or research materials. No other individuals employed or contracted by BMS (other than the named authors) played any role in: study design, data collection and analysis, or preparation of the manuscript. The specific roles of the authors are articulated in the ‘author contributions’ section. Nonauthors at BMS were involved in the decision to publish, for instance, in vetting the manuscript material for disclosure of proprietary information and approval of the timing of submission.