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Article ; Online: BNC210, a negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor, demonstrates anxiolytic- and antidepressant-like effects in rodents.

O'Connor, Susan M / Sleebs, Brad E / Street, Ian P / Flynn, Bernard L / Baell, Jonathan B / Coles, Carolyn / Quazi, Nurul / Paul, Dharam / Poiraud, Etienne / Huyard, Bertrand / Wagner, Stephanie / Andriambeloson, Emile / de Souza, Errol B

Neuropharmacology

2024 Volume 246, Page(s) 109836

Abstract: This work describes the characterization of BNC210 (6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(4-morpholinylcarbonyl)-1,8-naphthyridin-4(1H)-one), a selective, small molecule, negative allosteric modulator (NAM) of α7 nicotinic acetylcholine ... ...

Abstract	This work describes the characterization of BNC210 (6-[(2,3-dihydro-1H-inden-2-yl)amino]-1-ethyl-3-(4-morpholinylcarbonyl)-1,8-naphthyridin-4(1H)-one), a selective, small molecule, negative allosteric modulator (NAM) of α7 nicotinic acetylcholine receptors (α7 nAChR). With the aim to discover a non-sedating, anxiolytic compound, BNC210 was identified during phenotypic screening of a focused medicinal chemistry library using the mouse Light Dark (LD) box to evaluate anxiolytic-like activity and the mouse Open Field (OF) (dark) test to detect sedative and/or motor effects. BNC210 exhibited anxiolytic-like activity with no measurable sedative or motor effects. Electrophysiology showed that BNC210 did not induce α7 nAChR currents by itself but inhibited EC
MeSH term(s)	Rats ; Male ; Mice ; Humans ; Animals ; alpha7 Nicotinic Acetylcholine Receptor/metabolism ; Anti-Anxiety Agents/pharmacology ; Rodentia/metabolism ; Receptors, Nicotinic/metabolism ; Antidepressive Agents ; Hypnotics and Sedatives ; Allosteric Regulation
Chemical Substances	alpha7 Nicotinic Acetylcholine Receptor ; Anti-Anxiety Agents ; Receptors, Nicotinic ; Antidepressive Agents ; Hypnotics and Sedatives
Language	English
Publishing date	2024-01-06
Publishing country	England
Document type	Journal Article
ZDB-ID	218272-5
ISSN	1873-7064 ; 0028-3908
ISSN (online)	1873-7064
ISSN	0028-3908
DOI	10.1016/j.neuropharm.2024.109836
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Article ; Online: A perspective on the contribution of animal models to the pharmacological treatment of posttraumatic stress disorder.

Bertaina-Anglade, Valerie / O'Connor, Susan M / Andriambeloson, Emile

Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists

2017 Volume 25, Issue 4, Page(s) 342–347

Abstract: Objectives: Posttraumatic stress disorder (PTSD) is a prevalent, chronic, disabling disorder that may develop following exposure to a traumatic event. This review summarizes currently used animal models of PTSD and their potential role in the ... ...

Abstract	Objectives: Posttraumatic stress disorder (PTSD) is a prevalent, chronic, disabling disorder that may develop following exposure to a traumatic event. This review summarizes currently used animal models of PTSD and their potential role in the development of better therapeutics. Heterogeneity is one of the main characteristics of PTSD with the consequence that many pharmacological approaches are used to relieve symptoms of PTSD. To address the translational properties of the animal models, we discuss the types of stressors used, the rodent correlates of human PTSD (DSM-5) symptoms, and the efficacy of approved, recommended and off-label drugs used to treat PTSD in 'PTSD-animals'. Conclusions: Currently available animal models reproduce most PTSD symptoms and are validated by existing therapeutics. However, novel therapeutics are needed for this disorder as not one drug alleviates all symptoms and many have side effects that lead to non-compliance among PTSD patients. The true translational power of animal models of PTSD will only be demonstrated when new therapeutics acting through novel mechanisms become available for clinical practice.
MeSH term(s)	Animals ; Humans ; Models, Animal ; Stress Disorders, Post-Traumatic
Language	English
Publishing date	2017-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2213198-X
ISSN	1440-1665 ; 1039-8562
ISSN (online)	1440-1665
ISSN	1039-8562
DOI	10.1177/1039856217716288
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Article ; Online: Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder.

Perkins, Adam / Patrick, Fiona / Wise, Toby / Meyer, Nicholas / Mazibuko, Ndaba / Oates, Alice E / van der Bijl, Anne H M / Danjou, Philippe / O'Connor, Susan M / Doolin, Elizabeth / Wooldridge, Caroline / Rathjen, Deborah / Macare, Christine / Williams, Steven C R / Young, Allan H

Translational psychiatry

2021 Volume 11, Issue 1, Page(s) 13

Abstract: Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the ... ...

Abstract	Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy.
MeSH term(s)	Animals ; Anti-Anxiety Agents/pharmacology ; Anti-Anxiety Agents/therapeutic use ; Anxiety/drug therapy ; Anxiety Disorders/drug therapy ; Cholinergic Agents/therapeutic use ; Fear ; Female ; Humans ; Mice
Chemical Substances	Anti-Anxiety Agents ; Cholinergic Agents
Language	English
Publishing date	2021-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-020-01141-5
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Article ; Online: Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder.

Wise, Toby / Patrick, Fiona / Meyer, Nicholas / Mazibuko, Ndaba / Oates, Alice E / van der Bijl, Anne H M / Danjou, Philippe / O'Connor, Susan M / Doolin, Elizabeth / Wooldridge, Caroline / Rathjen, Deborah / Macare, Christine / Williams, Steven C R / Perkins, Adam / Young, Allan H

Biological psychiatry

2020 Volume 87, Issue 10, Page(s) 908–915

Abstract: Background: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefrontal networks, and normalization of this aberrant function is thought to be critical for successful treatment. Preclinical evidence implicates cholinergic ... ...

Abstract	Background: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefrontal networks, and normalization of this aberrant function is thought to be critical for successful treatment. Preclinical evidence implicates cholinergic neurotransmission in the function of these systems and suggests that cholinergic modulation may have anxiolytic effects. However, the effects of cholinergic modulators on the function of anxiety-related networks in humans have not been investigated. Methods: We administered a novel α7 nicotinic acetylcholine receptor-negative allosteric modulator, BNC210, to 24 individuals (3 male subjects) with generalized anxiety disorder and assessed its effects on neural responses to fearful face stimuli. Results: BNC210 reduced amygdala reactivity to fearful faces relative to placebo and similarly to lorazepam and also reduced connectivity between the amygdala and the anterior cingulate cortex, a network involved in regulating anxious responses to aversive stimuli. Conclusions: These results demonstrate for the first time that the function of disorder-relevant neural circuits in generalized anxiety disorder can be beneficially altered through modulation of cholinergic neurotransmission and suggest potential for this system as a novel target for anxiolytic pharmacotherapy.
MeSH term(s)	Amygdala ; Anxiety Disorders/drug therapy ; Cholinergic Agents ; Facial Expression ; Fear ; Humans ; Magnetic Resonance Imaging ; Male ; Prefrontal Cortex
Chemical Substances	Cholinergic Agents
Language	English
Publishing date	2020-01-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2019.12.013
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Article: The prediction of self-care behaviors in end-stage renal disease patients using Leventhal's Self-Regulatory Model.

O'Connor, Susan M / Jardine, Alan G / Millar, Keith

Journal of psychosomatic research

2008 Volume 65, Issue 2, Page(s) 191–200

Abstract: Objective: To assess the utility of Leventhal's Self-Regulatory Model (SRM) to predict self-care behavior with regard to dietary, medication, and fluid regimes in end-stage renal disease (ESRD) patients.: Methods: In a prospective study, ESRD ... ...

Abstract	Objective: To assess the utility of Leventhal's Self-Regulatory Model (SRM) to predict self-care behavior with regard to dietary, medication, and fluid regimes in end-stage renal disease (ESRD) patients. Methods: In a prospective study, ESRD patients treated via hospital-based haemodialysis (N=73) were screened for cognitive deficits and completed questionnaires that enquired about illness perceptions, coping strategies, knowledge of kidney disease, and psychological distress at Time 1. Physiological proxy measures of self-care behaviors regarding diet (serum potassium levels), fluid intake (mean and standard deviation of interdialytic weight gain), and medication (serum phosphate levels) regimes were collected 3 weeks later at Time 2. Results: Illness representations (emotional and timeline perceptions) predicted self-care behaviors with regard to diet and medication. Emotion-focused coping strategies predicted higher levels of variation in adherence to fluid restrictions. Younger males were less likely to adhere to the fluid restrictions. Conclusions: The SRM has predictive utility. Psychological interventions should focus on alleviating disease-specific distress and challenging erroneous timeline perceptions in order to increase adherence to dietary and medication regimes in ESRD patients. A more specific measure of coping for ESRD is required to clarify the role of coping strategies in this population. Younger, male patients should be targeted for extra support with fluid restrictions.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Drinking/physiology ; Feeding Behavior ; Female ; Humans ; Illness Behavior ; Internal-External Control ; Kidney Failure, Chronic/blood ; Kidney Failure, Chronic/psychology ; Kidney Failure, Chronic/therapy ; Male ; Mental Status Schedule ; Middle Aged ; Models, Psychological ; Patient Compliance/psychology ; Personality Inventory ; Phosphates/blood ; Potassium/blood ; Prospective Studies ; Renal Dialysis/psychology ; Self Care/psychology ; Sick Role ; Weight Gain/physiology ; Young Adult
Chemical Substances	Phosphates ; Potassium (RWP5GA015D)
Language	English
Publishing date	2008-08
Publishing country	England
Document type	Journal Article
ZDB-ID	80166-5
ISSN	1879-1360 ; 0022-3999
ISSN (online)	1879-1360
ISSN	0022-3999
DOI	10.1016/j.jpsychores.2008.02.008
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Article ; Online: Galantamine is not a positive allosteric modulator of human α4β2 or α7 nicotinic acetylcholine receptors.

Kowal, Natalia M / Ahring, Philip K / Liao, Vivian W Y / Indurti, Dinesh C / Harvey, Benjamin S / O'Connor, Susan M / Chebib, Mary / Olafsdottir, Elin S / Balle, Thomas

British journal of pharmacology

2018 Volume 175, Issue 14, Page(s) 2911–2925

Abstract: Background and purpose: The alkaloid galantamine was originally isolated from the green snowdrop Galanthus woronowii and is currently marketed as a drug for treatment of mild to moderate dementia in patients with Alzheimer's disease. In addition to a ... ...

Abstract	Background and purpose: The alkaloid galantamine was originally isolated from the green snowdrop Galanthus woronowii and is currently marketed as a drug for treatment of mild to moderate dementia in patients with Alzheimer's disease. In addition to a well-documented proficiency to inhibit acetylcholinesterase, galantamine has been reported to increase neuronal nicotinic ACh (nACh) receptor function by acting as a positive allosteric modulator. Yet there remains controversy regarding these findings in the literature. To resolve this conundrum, we evaluated galantamine actions at α4β2 and α7, which represent the nACh receptors most commonly associated with mammalian cognitive domains. Experimental approach: α4β2 [in (α4) Key results: In concentrations ranging from 10 nM to 1 μM, galantamine did not display direct agonism nor positive modulatory effects at any receptor combination tested. At concentrations from 10 μM and above, galantamine inhibited the activity with a mechanism of action consistent with open-channel pore blockade at all receptor types. Conclusion and implications: Based on our data, we conclude that galantamine is not a positive allosteric modulator of α7 or α4β2 receptors, which represent the majority of nACh receptors in mammalian brain.
MeSH term(s)	Allosteric Regulation ; Animals ; Cholinesterase Inhibitors/pharmacology ; Galantamine/pharmacology ; HEK293 Cells ; Humans ; Oocytes ; Receptors, Nicotinic/physiology ; Xenopus laevis ; alpha7 Nicotinic Acetylcholine Receptor/physiology
Chemical Substances	Cholinesterase Inhibitors ; Receptors, Nicotinic ; alpha7 Nicotinic Acetylcholine Receptor ; nicotinic receptor alpha4beta2 ; Galantamine (0D3Q044KCA)
Language	English
Publishing date	2018-06-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.14329
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Article: Discovery of BNC375, a Potent, Selective, and Orally Available Type I Positive Allosteric Modulator of α7 nAChRs.

Harvey, Andrew J / Avery, Thomas D / Schaeffer, Laurent / Joseph, Christophe / Huff, Belinda C / Singh, Rajinder / Morice, Christophe / Giethlen, Bruno / Grishin, Anton A / Coles, Carolyn J / Kolesik, Peter / Wagner, Stéphanie / Andriambeloson, Emile / Huyard, Bertrand / Poiraud, Etienne / Paul, Dharam / O'Connor, Susan M

ACS medicinal chemistry letters

2019 Volume 10, Issue 5, Page(s) 754–760

Abstract: Positive allosteric modulators (PAMs) of α7 nAChRs can have different properties with respect to their effects on channel kinetics. Type I PAMs amplify peak channel response to acetylcholine but do not appear to influence channel desensitization kinetics, ...

Abstract	Positive allosteric modulators (PAMs) of α7 nAChRs can have different properties with respect to their effects on channel kinetics. Type I PAMs amplify peak channel response to acetylcholine but do not appear to influence channel desensitization kinetics, whereas Type II PAMs both increase channel response and delay receptor desensitization. Both Type I and Type II PAMs are reported in literature, but there are limited reports describing their structure-kinetic profile relationships. Here, we report a novel class of compounds with either Type I or Type II behavior that can be tuned by the relative stereochemistry around the central cyclopropyl ring: for example, (
Language	English
Publishing date	2019-03-25
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.9b00001
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Article ; Online: A bioassay for the detection of perchlorate in the ppb range.

Heinnickel, Mark / Smith, Stephen C / Koo, Jonathan / O'Connor, Susan M / Coates, John D

Environmental science & technology

2011 Volume 45, Issue 7, Page(s) 2958–2964

Abstract: A bioassay for the determination of ppb (μg·L(-1)) concentrations of perchlorate has been developed and is described herein. The assay uses the enzyme perchlorate reductase (PR) from the perchlorate-reducing organism Dechloromonas agitata in purified and ...

Abstract	A bioassay for the determination of ppb (μg·L(-1)) concentrations of perchlorate has been developed and is described herein. The assay uses the enzyme perchlorate reductase (PR) from the perchlorate-reducing organism Dechloromonas agitata in purified and partially purified forms to detect perchlorate. The redox active dye phenazine methosulfate (PMS) is shown to efficiently shuttle electrons to PR from NADH. Perchlorate can be determined indirectly by monitoring NADH oxidization by PR. To lower the detection limit, we have shown that perchlorate can be concentrated on a solid-phase extraction (SPE) column that is pretreated with the cation decyltrimethylammonium bromide (DTAB). Perchlorate is eluted from these columns with a solution of 2 M NaCl and 200 mM morpholine propane sulfonic acid (MOPS, pH 12.5). By washing these columns with 15 mL of 2.5 mM DTAB and 15% acetone, contaminating ions, such as chlorate and nitrate, are removed without affecting the bioassay. Because of the effect of complex matrices on the SPE columns, the method of standard additions is used to analyze tap water and groundwater samples. The efficacy of the developed bioassay was demonstrated by analyzing samples from 2-17000 ppb in deionized lab water, tap water, and contaminated groundwater.
MeSH term(s)	Biological Assay ; Environmental Monitoring/methods ; NAD/analysis ; NAD/metabolism ; Oxidoreductases/analysis ; Oxidoreductases/metabolism ; Perchlorates/analysis ; Perchlorates/metabolism ; Rhodocyclaceae/enzymology ; Water Pollutants, Chemical/analysis ; Water Pollutants, Chemical/metabolism ; Water Supply/analysis
Chemical Substances	Perchlorates ; Water Pollutants, Chemical ; NAD (0U46U6E8UK) ; Oxidoreductases (EC 1.-) ; perchlorate (VLA4NZX2P4)
Language	English
Publishing date	2011-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1520-5851
ISSN (online)	1520-5851
DOI	10.1021/es103715f
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Article ; Online: Pharmacological Characterization of the Novel and Selective

Wang, Xiaohai / Daley, Christopher / Gakhar, Vanita / Lange, Henry S / Vardigan, Joshua D / Pearson, Michelle / Zhou, Xiaoping / Warren, Lee / Miller, Corin O / Belden, Michelle / Harvey, Andrew J / Grishin, Anton A / Coles, Carolyn J / O'Connor, Susan M / Thomson, Fiona / Duffy, Joseph L / Bell, Ian M / Uslaner, Jason M

The Journal of pharmacology and experimental therapeutics

2020 Volume 373, Issue 2, Page(s) 311–324

Abstract: Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. ... ...

Abstract	Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The
MeSH term(s)	Allosteric Regulation ; Animals ; Benzethonium/pharmacology ; Brain/drug effects ; Brain/physiology ; Cell Survival/drug effects ; Cells, Cultured ; Chlorobenzenes/pharmacology ; Cognition/drug effects ; Long-Term Potentiation/drug effects ; Macaca mulatta ; Male ; Neurotransmitter Agents/metabolism ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Scopolamine/pharmacology ; alpha7 Nicotinic Acetylcholine Receptor/agonists
Chemical Substances	BNC375 ; Chlorobenzenes ; Neurotransmitter Agents ; alpha7 Nicotinic Acetylcholine Receptor ; Benzethonium (1VU15B70BP) ; Scopolamine (DL48G20X8X)
Language	English
Publishing date	2020-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.119.263483
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Article: Anaerobic degradation of benzene, toluene, ethylbenzene, and xylene compounds by Dechloromonas strain RCB.

Chakraborty, Romy / O'Connor, Susan M / Chan, Emily / Coates, John D

Applied and environmental microbiology

2005 Volume 71, Issue 12, Page(s) 8649–8655

Abstract: Dechloromonas strain RCB has been shown to be capable of anaerobic degradation of benzene coupled to nitrate reduction. As a continuation of these studies, the metabolic versatility and hydrocarbon biodegradative capability of this organism were ... ...

Abstract	Dechloromonas strain RCB has been shown to be capable of anaerobic degradation of benzene coupled to nitrate reduction. As a continuation of these studies, the metabolic versatility and hydrocarbon biodegradative capability of this organism were investigated. The results of these revealed that in addition to nitrate, strain RCB could alternatively degrade benzene both aerobically and anaerobically with perchlorate or chlorate [(per)chlorate] as a suitable electron acceptor. Furthermore, with nitrate as the electron acceptor, strain RCB could also utilize toluene, ethylbenzene, and all three isomers of xylene (ortho-, meta-, and para-) as electron donors. While toluene and ethylbenzene were completely mineralized to CO2, strain RCB did not completely mineralize para-xylene but rather transformed it to some as-yet-unidentified metabolite. Interestingly, with nitrate as the electron acceptor, strain RCB degraded benzene and toluene concurrently when the hydrocarbons were added as a mixture and almost 92 microM total hydrocarbons were oxidized within 15 days. The results of these studies emphasize the unique metabolic versatility of this organism, highlighting its potential applicability to bioremediative technologies.
MeSH term(s)	Anaerobiosis ; Benzene/metabolism ; Benzene Derivatives/metabolism ; Betaproteobacteria/metabolism ; Biotransformation ; Electron Transport ; Kinetics ; Toluene/metabolism ; Xylenes/metabolism
Chemical Substances	Benzene Derivatives ; Xylenes ; Toluene (3FPU23BG52) ; Benzene (J64922108F) ; ethylbenzene (L5I45M5G0O)
Language	English
Publishing date	2005-12
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	223011-2
ISSN	1098-5336 ; 0099-2240
ISSN (online)	1098-5336
ISSN	0099-2240
DOI	10.1128/AEM.71.12.8649-8655.2005
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