BMS-933043, a Selective α7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia.
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ABSTRACT:
SUBMITTER: King D
PROVIDER: S-EPMC5346989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC4965148 | biostudies-literature
Project description:Background and purposeActivation of the α7 nicotinic ACh receptor (nACh receptor) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel α7-nACh receptor agonist AQW051 as a promising drug candidate for this indication.Experimental approachAQW051 was functionally characterized in vitro and cognitive effects evaluated in rodent behavioural models. Pharmacokinetics and tolerability were evaluated in three phase I placebo-controlled studies in 180 healthy subjects.Key resultsIn vitro, AQW051 bound with high affinity to α7-nACh receptors and stimulated calcium influx in cells recombinantly expressing the human α7-nACh receptor. In vivo, AQW051 demonstrated good oral bioavailability and rapid penetration into the rodent brain. AQW051 administered over a broad dose range facilitated learning/memory performance in the object recognition and social recognition test in mice and the water maze model in aged rats. Clinically, AQW051 was well tolerated in healthy young and elderly subjects, with an adverse event (AE) profile comparable with placebo. No serious AEs were reported and all AEs were either mild or moderate in severity at single oral doses up to 200 mg and multiple daily doses up to 75 mg. Once-daily oral administration of AQW051 resulted in continuous exposure and a two- to threefold accumulation compared with steady state was achieved by 1 week.Conclusions and implicationsThese data support further development of AQW051 as a cognitive-enhancing agent, as a therapeutic, for example, in Alzheimer's disease or schizophrenia.
| S-EPMC4337702 | biostudies-literature
Project description:Encenicline is a novel, selective α7 nicotinic acetylcholine receptor agonist in development for treating cognitive impairment in schizophrenia and Alzheimer's disease. A phase 2, double-blind, randomized, placebo-controlled, parallel-design, multinational study was conducted. Patients with schizophrenia on chronic stable atypical antipsychotics were randomized to encenicline 0.27 or 0.9 mg once daily or placebo for 12 weeks. The primary efficacy end point was the Overall Cognition Index (OCI) score from the CogState computerized battery. Secondary end points include MATRICS Consensus Cognitive Battery (MCCB) (in US patients), the Schizophrenia Cognition Rating Scale (SCoRS) total score, SCoRS global rating, and Positive and Negative Syndrome Scale (PANSS) total and subscale and cognition factor scores. Of 319 randomized patients, 317 were included in the safety population, and 307 were included in the intent-to-treat population. Notable trends in improvement were demonstrated across all cognition scales. For the OCI score, the LS mean difference for encenicline 0.27 mg vs placebo was significant (Cohen's d=0.257; P=0.034). Mean SCoRS total scores decreased showing improvement in function over time, and the difference was significant for encenicline 0.9 mg vs placebo (P=0.011). Furthermore, the difference between encenicline 0.9 mg and placebo was significant for the PANSS Cognition Impairment Domain (P=0.0098, Cohen's d=0.40) and for the PANSS Negative scale (P=0.028, Cohen's d=0.33). Treatment-emergent adverse events were reported at similar frequencies across all treatment groups (39.0% with placebo, 23.4% with encenicline 0.27 mg, and 33.3% with encenicline 0.9 mg). Overall, encenicline was generally well tolerated and demonstrated clinically meaningful improvements in cognition and function in patients with schizophrenia.
| S-EPMC4864641 | biostudies-literature
Project description:The α7 nicotinic acetylcholine receptor (nAChR) is an important target given its role in cognitive function as well as in the cholinergic anti-inflammatory pathway, where ligands that are effective at stabilizing desensitized states of the receptor are of particular interest. The typical structural element associated with a good desensitizer is the ammonium pharmacophore, but recent work has identified that a trivalent sulfur, in the positively charged sulfonium form, can substitute for the nitrogen in the ammonium pharmacophore. However, the breadth and scope of employing the sulfonium group is largely unexplored. In this work, we have surveyed a disparate group of sulfonium compounds for their functional activity with α7 as well as other nAChR subtypes. Amongst them, we found that there is a wide range of ability to induce α7 desensitization, with 4-hydroxyphenyldimethylsulfonium and suplatast sulfonium salts being the most desensitizing. The smallest sulfonium compound, trimethylsulfonium, was a partial agonist for α7 and other neuronal nAChR. Molecular docking into the α7 receptor extracellular domain revealed preferred poses in the orthosteric binding site for all but one compound, with typical cation-pi interactions as seen with traditional ammonium compounds. A number of the compounds tested may serve as useful platforms for further development of α7 desensitizing ability and for receptor subtype selectivity.
| S-EPMC8464850 | biostudies-literature
Project description:Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) is critical for the pathogenesis of Escherichia coli (E. coli) K1 meningitis, a severe central nervous system infection of the neonates. However, little is known about how E. coli K1 manipulates α7 nAChR signaling. Here, through employing immortalized cell lines, animal models, and human transcriptional analysis, we showed that E. coli K1 infection triggers releasing of secreted Ly6/Plaur domain containing 1 (SLURP1), an endogenous α7 nAChR ligand. Exogenous supplement of SLURP1, combined with SLURP1 knockdown or overexpression cell lines, showed that SLURP1 is required for E. coli K1 invasion and neutrophils migrating across the blood-brain barrier (BBB). Furthermore, we found that SLURP1 is required for E. coli K1-induced α7 nAChR activation. Finally, the promoting effects of SLURP1 on the pathogenesis of E. coli K1 meningitis was significantly abolished in the α7 nAChR knockout mice. These results reveal that E. coli K1 exploits SLURP1 to activate α7 nAChR and facilitate its pathogenesis, and blocking SLURP1-α7 nAChR interaction might represent a novel therapeutic strategy for E. coli K1 meningitis.
| S-EPMC8552013 | biostudies-literature
Project description:A double-blind, placebo-controlled, parallel-group, 24-week, multicenter trial was conducted to evaluate the efficacy and safety of 3 doses of ABT-126, an α7 nicotinic receptor agonist, for the treatment of cognitive impairment in nonsmoking subjects with schizophrenia. Clinically stable subjects were randomized in 2 stages: placebo, ABT-126 25 mg, 50 mg or 75 mg once daily (stage 1) and placebo or ABT-126 50 mg (stage 2). The primary analysis was the change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score for ABT-126 50 mg vs placebo using a mixed-model for repeated-measures. A key secondary measure was the University of California Performance-based Assessment-Extended Range (UPSA-2ER). A total of 432 subjects were randomized and 80% (344/431) completed the study. No statistically significant differences were observed in either the change from baseline for the MCCB neurocognitive composite score (+2.66 [±0.54] for ABT-126 50 mg vs +2.46 [±0.56] for placebo at week 12; P>0.05) or the UPSA-2ER. A trend for improvement was seen at week 24 on the 16-item Negative Symptom Assessment Scale total score for ABT-126 50 mg (change from baseline -4.27±[0.58] vs -3.00±[0.60] for placebo; P=0.059). Other secondary analyses were generally consistent with the primary end point results. Adverse event rates were similar for ABT-126 and placebo. ABT-126 did not demonstrate a consistent effect on cognition in nonsmoking subjects with schizophrenia; however, a trend toward an effect was observed on negative symptoms. ClincalTrials.gov registration: NCT01655680.
| S-EPMC5061881 | biostudies-literature
Project description:Background:The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition. Methods:We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia. Results:Test-retest PET confirmed reproducibility (>90%) (variability ≤7%) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test). Conclusions:The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.
| S-EPMC6030963 | biostudies-literature
Project description:Effective treatments for cognitive impairment associated with schizophrenia (CIAS) remain an unmet need. Nicotinic ?7 receptor agonists may be effective in CIAS. This 8-week (week 1, inpatient; weeks 2-8, outpatient), double-blind, randomized study used Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) guidelines to investigate the nicotinic ?7 partial agonist RG3487 (formerly MEM3454) in CIAS; 215 patients with chronic stable schizophrenia received placebo or RG3487 (5, 15, or 50 mg) added to ongoing treatment with risperidone, paliperidone, or aripiprazole. Primary end point was baseline to week 8 change in MATRICS Consensus Cognitive Battery (MCCB) composite t-score. Secondary outcomes were change in MCCB domain and negative symptom assessment (NSA) scores. The study did not allow for evaluation of nonsmokers. Each RG3487 dose was evaluated using a mixed-effects model repeated measures approach. Mean (SD) baseline MCCB composite t-score was 28.3 (12.0). No significant effect on MCCB composite t-scores was observed with RG3487 (adjusted mean difference (SE) vs placebo: 5 mg: 0.11 (1.39); 15 mg: -1.95 (1.39); 50 mg: -1.13 (1.37); p = 0.2-0.9). RG3487 did not improve MCCB domain scores. In a post hoc analysis of patients with moderate negative symptoms, 5 and 50 mg RG3487 vs placebo significantly improved NSA total (-4.45 (p = 0.04) and -4.75 (p = 0.02), respectively) and global (-0.39 (p = 0.04) and -0.55 (p = 0.003), respectively) scores. The MCCB did not lead to higher than expected patient withdrawal. RG3487 was generally well tolerated. In patients with stable schizophrenia, RG3487 did not improve cognitive deficits, as assessed by the MCCB; however, in patients with moderate negative symptoms, a post hoc analysis revealed significant improvement of negative symptoms.
| S-EPMC4023143 | biostudies-other
Project description:Background and purposeMany of the addictive and rewarding effects of nicotine are due to its actions on the neuronal nicotinic ACh receptor (nAChR) subtypes expressed in dopaminergic mesocorticolimbic cells. The partial agonists, cytisine and varenicline, are helpful smoking cessation aids. These drugs have a number of side effects that limit their usefulness. The aim of this study was to investigate the preclinical pharmacology of the cytisine dimer1,2-bisN-cytisinylethane (CC4).Experimental approachThe effects of CC4 on nAChRs were investigated using in vitro assays and animal behaviours.Key resultsWhen electrophysiologically tested using heterologously expressed human subtypes, CC4 was less efficacious than cytisine on neuronal ?4?2, ?3?4, ?7 and muscle-type receptors, and had no effect on 5-hydroxytryptamine3 receptors. Acting through ?4?2 and ?6?2 nAChRs, CC4 is a partial agonist of nAChR-mediated striatal dopamine release and, when co-incubated with nicotine, prevented nicotine's maximal effect on this response. In addition, it had low affinity for, and was less efficacious than nicotine and cytisine on the ?3?4 and ?7-nAChR subtypes. Like cytisine and nicotine, CC4-induced conditioned place preference (CPP), and its self-administration shows an inverted-U dose-response curve. Pretreatment with non-reinforcing doses of CC4 significantly reduced nicotine-induced self-administration and CPP without affecting motor functions.Conclusion and implicationsOur in vitro and in vivo findings reveal that CC4 selectively reduces behaviours associated with nicotine addiction consistent with the partial agonist selectivity of CC4 for ?2-nAChRs. The results support the possible development of CC4 or its derivatives as a promising drug for tobacco smoking cessation.
| S-EPMC3631374 | biostudies-literature
Project description:BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) ? agonist, with an EC50 of 4 nM for human PPAR? and >1000-fold selectivity vs human PPAR? (EC50 = 4.5 ?M) and PPAR? (EC50 > 100 ?M) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.
| S-EPMC4904259 | biostudies-literature