BMS-933043 improves 24 h recognition memory in mice.

<p>Subjects were treated 30 min prior to the training session with either A/B) vehicle or low doses of BMS-933043 (n = 11–13/group), C/D) vehicle or high doses of BMS-933043 (n = 10–13/group) or E/F) vehicle or NS-6740 (10 mg/kg, sc) 10 min prior to BMS-933043 (0.3 mg/kg, sc; n = 15–16/group) and then tested for memory retention 24 h later. Results are presented as the mean ± SEM % discrimination index for the training (A, C, E) and test sessions (B, D, F) and were analyzed by ANOVA followed by Dunnett’s test; ** p<0.01, *** p<0.001 versus vehicle or vehicle/BMS-933043 treated mice.</p

Functional efficacy at recombinant human α7 nACh and 5-HT_3A receptors determined by Ca²⁺ flux (FLIPR) assays.

<p>Functional efficacy at recombinant human α7 nACh and 5-HT_3A receptors determined by Ca²⁺ flux (FLIPR) assays.</p

BMS-933043 improves EDS performance in neonatal PCP-treated rats.

<p>Results are presented as the mean ± SEM number of trials required to reach the performance criterion of 6 successive correct entries into the baited pot for each discrimination (n = 9–10/treatment). Results were analyzed by 2 way repeated measures ANOVA followed by Dunnett’s post hoc analysis; **** p = 0.0001 compared to neonatal PCP/Vehicle treated rats.</p

Summary of BMS-933043 Results in Preclinical Models of Schizophrenia.

<p>Summary of BMS-933043 Results in Preclinical Models of Schizophrenia.</p

BMS-933043 improves MMN in neonatal PCP-treated rats.

<p>Results from 3 independent studies are presented as the mean ± SEM AUC determined from the averaged difference wave for each subject after treatment with either vehicle or BMS-933043 (n = 12–13/group). For reference, the dashed line shows the average AUC in untreated adult rats determined in separate studies. Each treatment was analyzed by one sample, two tailed t test; ** p<0.01 compared to a hypothetical zero.</p

Displacement of [³H]-A-585539 binding to rat brain or recombinant human α7 nAChR.

<p>Displacement of [³H]-A-585539 binding to rat brain or recombinant human α7 nAChR.</p

Relationship between dose, plasma exposure and ex vivo α7 nAChR occupancy in rodents.

<p>A) Results show the mean ± SEM occupancy determined 30 min after sc dosing in mice (open circles) or 90 min after po dosing in rats (n = 4/dose). B) Individual occupancy/exposure results for mice (open circles) and composite plot showing results for rats (closed circles) treated po (as above), sc (30 min post-dose) and experimental set shift subjects (150 min post-dose).</p

Molecular structure of BMS-933043.

<p>Molecular structure of BMS-933043.</p

Partial agonist profile of BMS-933043 and inhibition by NS-6740 in whole cell voltage clamp electrophysiology.

<p>A) Results show the mean ± SEM peak current response (open symbols) or net charge crossing the membrane (closed symbols) at rat (circles; n = 4) and human (squares; n = 7) α7 nAChR. B) Results show the mean ± SEM net charge crossing the membrane following BMS-933043 (10 μM) application in the presence of increasing concentrations of NS-6740 (n = 6). All results were normalized to the maximal response elicited by ACh.</p

Reversal of MK-801-induced deficits in 2 trial Y maze performance in mice.

<p>Results from the free-choice trial are presented as the mean ± SEM % time spent in the novel arm (n = 16–18/treatment) and were analyzed by ANOVA followed by Dunnett’s post hoc analysis; ** p<0.01, *** p<0.001 versus vehicle/MK-801 treatment.</p