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

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

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 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

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

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

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

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

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