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

• DOI: 10.1371/journal.pone.0159996
• Publication Date: 2016-07-28T18:04:58Z
• Authors: 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
• Keywords: Male; Quinuclidines; Patch-Clamp Techniques; alpha7 Nicotinic Acetylcholine Receptor; Science; Q; R; Drug Evaluation, Preclinical; Rats; 3. Good health; Mice; Radioligand Assay; 03 medical and health sciences; HEK293 Cells; 0302 clinical medicine; Schizophrenia; Medicine; Animals; Humans; Spiro Compounds; Cognition Disorders; Research Article

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