Hajos M

General

Full name : Hajos Mihaly

First name : Mihaly

Mail : University Dept. of Pharmacology, Mansfield Road, Oxford OXl 3QT

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Country : United Kingdom

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Phone : (44) 865 271850

Fax : (44) 865 271853

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References (13)

Title : Treatment effects on event-related EEG potentials and oscillations in Alzheimer's disease - Yener_2022_Int.J.Psychophysiol__
Author(s) : Yener G , Hunerli-Gunduz D , Yildirim E , Akturk T , Basar-Eroglu C , Bonanni L , Del Percio C , Farina F , Ferri R , Guntekin B , Hajos M , Ibanez A , Jiang Y , Lizio R , Lopez S , Noce G , Parra M , Randall F , Stocchi F , Babiloni C
Ref : Int J Psychophysiol , : , 2022
Abstract : Alzheimer's disease dementia (ADD) is the most diffuse neurodegenerative disorder belonging to mild cognitive impairment (MCI) and dementia in old persons. This disease is provoked by an abnormal accumulation of amyloid-beta and tauopathy proteins in the brain. Very recently, the first disease-modifying drug has been licensed with reserve (i.e., Aducanumab). Therefore, there is a need to identify and use biomarkers probing the neurophysiological underpinnings of human cognitive functions to test the clinical efficacy of that drug. In this regard, event-related electroencephalographic potentials (ERPs) and oscillations (EROs) are promising candidates. Here, an Expert Panel from the Electrophysiology Professional Interest Area of the Alzheimer's Association and Global Brain Consortium reviewed the field literature on the effects of the most used symptomatic drug against ADD (i.e., Acetylcholinesterase inhibitors) on ERPs and EROs in ADD patients with MCI and dementia at the group level. The most convincing results were found in ADD patients. In those patients, Acetylcholinesterase inhibitors partially normalized ERP P300 peak latency and amplitude in oddball paradigms using visual stimuli. In these same paradigms, those drugs partially normalize ERO phase-locking at the theta band (4-7 Hz) and spectral coherence between electrode pairs at the gamma (around 40 Hz) band. These results are of great interest and may motivate multicentric, double-blind, randomized, and placebo-controlled clinical trials in MCI and ADD patients for final cross-validation.
ESTHER : Yener_2022_Int.J.Psychophysiol__
PubMedSearch : Yener_2022_Int.J.Psychophysiol__
PubMedID: 35588964

Title : Concentration-response relationship of the alpha7 nicotinic acetylcholine receptor agonist FRM-17874 across multiple in vitro and in vivo assays - Stoiljkovic_2015_Biochem.Pharmacol_97(4)_576
Author(s) : Stoiljkovic M , Leventhal L , Chen A , Chen T , Driscoll R , Flood D , Hodgdon H , Hurst R , Nagy D , Piser T , Tang C , Townsend M , Tu Z , Bertrand D , Koenig G , Hajos M
Ref : Biochemical Pharmacology , 97 :576 , 2015
Abstract : Pharmacological activation of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) may improve cognition in schizophrenia and Alzheimer's disease. The present studies describe an integrated pharmacological analysis of the effects of FRM-17874, an analogue of encenicline, on alpha7 nAChRs in vitro and in behavioral and neurophysiological assays relevant to cognitive function. FRM-17874 demonstrated high affinity binding to human alpha7 nAChRs, displacing [(3)H]-methyllacaconitine (Ki=4.3nM). In Xenopus laevis oocytes expressing human alpha7 nAChRs, FRM-17874 acted as an agonist, evoking inward currents with an EC50 of 0.42muM. Lower concentrations of FRM-17874 (0.01-3nM) elicited no detectable current, but primed receptors to respond to sub-maximal concentrations of acetylcholine. FRM-17874 improved novel object recognition in rats, and enhanced memory acquisition and reversal learning in the mouse water T-maze. Neurophysiological correlates of cognitive effects of drug treatment, such as synaptic transmission, long-term potentiation, and hippocampal theta oscillation were also evaluated. Modulation of synaptic transmission and plasticity was observed in rat hippocampal slices at concentrations of 3.2 and 5nM. FRM-17874 showed a dose-dependent facilitation of stimulation-induced hippocampal theta oscillation in mice and rats. The FRM-17874 unbound brain concentration-response relationship for increased theta oscillation power was similar in both species, exhibited a biphasic pattern peaking around 3nM, and overlapped with active doses and exposures observed in cognition assays. In summary, behavioral and neurophysiological assays indicate a bell-shaped effective concentration range and this report represents the first attempt to explain the concentration-response function of alpha7 nAChR-mediated pro-cognitive effects in terms of receptor pharmacology.
ESTHER : Stoiljkovic_2015_Biochem.Pharmacol_97(4)_576
PubMedSearch : Stoiljkovic_2015_Biochem.Pharmacol_97(4)_576
PubMedID: 26206187

Title : Modulation of hippocampal neuronal network oscillations by alpha7 nACh receptors - Stoiljkovic_2015_Biochem.Pharmacol_97(4)_445
Author(s) : Stoiljkovic M , Kelley C , Nagy D , Hajos M
Ref : Biochemical Pharmacology , 97 :445 , 2015
Abstract : Synchronization of neuronal network oscillations within the cortex and hippocampus has been closely linked to various cognitive domains, including attention, learning, and memory. The frequency, power, and connectivity of hippocampal oscillations provide quantitative measures for examining the modulation of network activity, which influences mnemonic functions and memory formation. The wide distribution of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) throughout the hippocampus makes them well positioned to modulate neuronal network activity. Elicitation of hippocampal theta through high frequency stimulation of the brainstem nucleus pontis oralis (nPO) is shown to be sensitive to several agents exhibiting pharmacological effects on cognition, thus representing a suitable preclinical screening assay for such drugs, including alpha7 nAChR agonists. We hypothesize that increases in theta power and theta-phase gamma-amplitude coupling due to alpha7 nAChR agonists during elicited hippocampal oscillations could reflect changes in synchronous activity of pyramidal neurons which is a critical factor for hippocampal-dependent cognitive function. In this review, four major topics are discussed: neuronal network oscillations in the hippocampus, the characteristics and distribution of alpha7 nAChRs therein, the modulation of elicited hippocampal theta and gamma oscillations by alpha7 nAChR agonists, as well as potential intrinsic roles of alpha7 nAChRs in hippocampal oscillations using alpha7 nAChR knock-out mice.
ESTHER : Stoiljkovic_2015_Biochem.Pharmacol_97(4)_445
PubMedSearch : Stoiljkovic_2015_Biochem.Pharmacol_97(4)_445
PubMedID: 26206189

Title : Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models - O'Donnell_2010_J.Med.Chem_53_1222
Author(s) : O'Donnell CJ , Rogers BN , Bronk BS , Bryce DK , Coe JW , Cook KK , Duplantier AJ , Evrard E , Hajos M , Hoffmann WE , Hurst RS , Maklad N , Mather RJ , McLean S , Nedza FM , O'Neill BT , Peng L , Qian W , Rottas MM , Sands SB , Schmidt AW , Shrikhande AV , Spracklin DK , Wong DF , Zhang A , Zhang L
Ref : Journal of Medicinal Chemistry , 53 :1222 , 2010
Abstract : A novel alpha 7 nAChR agonist, 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (24, CP-810,123), has been identified as a potential treatment for cognitive deficits associated with psychiatric or neurological conditions including schizophrenia and Alzheimer's disease. Compound 24 is a potent and selective compound with excellent pharmaceutical properties. In rodent, the compound displays high oral bioavailability and excellent brain penetration affording high levels of receptor occupancy and in vivo efficacy in auditory sensory gating and novel object recognition. The structural diversity of this compound and its preclinical in vitro and in vivo package support the hypothesis that alpha 7 nAChR agonists may have potential as a pharmacotherapy for the treatment of cognitive deficits in schizophrenia.
ESTHER : O'Donnell_2010_J.Med.Chem_53_1222
PubMedSearch : O'Donnell_2010_J.Med.Chem_53_1222
PubMedID: 20043678

Title : Targeting alpha7 nicotinic acetylcholine receptors in the treatment of schizophrenia - Hajos_2010_Curr.Pharm.Des_16_538
Author(s) : Hajos M , Rogers BN
Ref : Curr Pharm Des , 16 :538 , 2010
Abstract : The most abundant homomeric nicotinic acetylcholine receptors (nAChRs) in the mammalian brain are the pentameric alpha7 nAChRs which consist of five alpha7 subunits, and each subunit provides an orthosteric low affinity binding site for its endogenous ligand, acetylcholine. Distribution and high level expression of alpha7 nAChRs within the limbic circuitry, including the hippocampus and prefrontal cortical areas are in line with their involvement in various cognitive functions. Activation of alpha7 nAChRs generates a conformational change of sub-unit proteins, making the channel permeable to cations, in particular calcium, leading to change in neuronal activity and excitability, and via increased intracellular calcium, modulating transmitter release and neuronal network activity. Since genetic linkage studies implicated the alpha7 nAChRs subunit gene CHRNA7 in schizophrenia, there is a considerable interest for developing drug therapies targeting alpha7 nAChRs. In this review recent development of selective agonists and positive allosteric modulators of alpha7 nAChRs are discussed. In addition to summarizing medicinal chemistry efforts, both cellular and neuronal network pharmacology of alpha7 nAChRs are covered. The association between CHRNA7 gene and impaired P50 auditory gating has provided an attractive endophenotype, and its use as a potential translational biomarker for alpha7 nAChRs drug discovery is discussed. Preliminary clinical findings on alpha7 nAChRs agonists are also summarized.
ESTHER : Hajos_2010_Curr.Pharm.Des_16_538
PubMedSearch : Hajos_2010_Curr.Pharm.Des_16_538
PubMedID: 19909231

Title : Preclinical pharmacology of the alpha4beta2 nAChR partial agonist varenicline related to effects on reward, mood and cognition - Rollema_2009_Biochem.Pharmacol_78(7)_813
Author(s) : Rollema H , Hajos M , Seymour PA , Kozak R , Majchrzak MJ , Guanowsky V , Horner WE , Chapin DS , Hoffmann WE , Johnson DE , McLean S , Freeman J , Williams KE
Ref : Biochemical Pharmacology , 78 :813 , 2009
Abstract : The pharmacological properties and pharmacokinetic profile of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline provide an advantageous combination of free brain levels and functional potencies at the target receptor that for a large part explain its efficacy as a smoking cessation aid. Since alpha4beta2 and other nAChR subtypes play important roles in mediating central processes that control reward, mood, cognition and attention, there is interest in examining the effects of selective nAChR ligands such as varenicline in preclinical animal models that assess these behaviors. Here we describe results from studies on varenicline's effects in animal models of addiction, depression, cognition and attention and discuss these in the context of recently published preclinical and preliminary clinical studies that collected data on varenicline's effects on mood, cognition and alcohol abuse disorder. Taken together, the preclinical and the limited clinical data show beneficial effects of varenicline, but further clinical studies are needed to evaluate whether the preclinical effects observed in animal models are translatable to the clinic.
ESTHER : Rollema_2009_Biochem.Pharmacol_78(7)_813
PubMedSearch : Rollema_2009_Biochem.Pharmacol_78(7)_813
PubMedID: 19501054

Title : Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity - Acker_2008_Bioorg.Med.Chem.Lett_18_3611
Author(s) : Acker BA , Jacobsen EJ , Rogers BN , Wishka DG , Reitz SC , Piotrowski DW , Myers JK , Wolfe ML , Groppi VE , Thornburgh BA , Tinholt PM , Walters RR , Olson BA , Fitzgerald L , Staton BA , Raub TJ , Krause M , Li KS , Hoffmann WE , Hajos M , Hurst RS , Walker DP
Ref : Bioorganic & Medicinal Chemistry Lett , 18 :3611 , 2008
Abstract : A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.
ESTHER : Acker_2008_Bioorg.Med.Chem.Lett_18_3611
PubMedSearch : Acker_2008_Bioorg.Med.Chem.Lett_18_3611
PubMedID: 18490160

Title : Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists - Walker_2006_Bioorg.Med.Chem_14_8219
Author(s) : Walker DP , Wishka DG , Piotrowski DW , Jia S , Reitz SC , Yates KM , Myers JK , Vetman TN , Margolis BJ , Jacobsen EJ , Acker BA , Groppi VE , Wolfe ML , Thornburgh BA , Tinholt PM , Cortes-Burgos LA , Walters RR , Hester MR , Seest EP , Dolak LA , Han F , Olson BA , Fitzgerald L , Staton BA , Raub TJ , Hajos M , Hoffmann WE , Li KS , Higdon NR , Wall TM , Hurst RS , Wong EH , Rogers BN
Ref : Bioorganic & Medicinal Chemistry , 14 :8219 , 2006
Abstract : A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
ESTHER : Walker_2006_Bioorg.Med.Chem_14_8219
PubMedSearch : Walker_2006_Bioorg.Med.Chem_14_8219
PubMedID: 17011782

Title : Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship - Wishka_2006_J.Med.Chem_49_4425
Author(s) : Wishka DG , Walker DP , Yates KM , Reitz SC , Jia S , Myers JK , Olson KL , Jacobsen EJ , Wolfe ML , Groppi VE , Hanchar AJ , Thornburgh BA , Cortes-Burgos LA , Wong EH , Staton BA , Raub TJ , Higdon NR , Wall TM , Hurst RS , Walters RR , Hoffmann WE , Hajos M , Franklin S , Carey G , Gold LH , Cook KK , Sands SB , Zhao SX , Soglia JR , Kalgutkar AS , Arneric SP , Rogers BN
Ref : Journal of Medicinal Chemistry , 49 :4425 , 2006
Abstract : N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
ESTHER : Wishka_2006_J.Med.Chem_49_4425
PubMedSearch : Wishka_2006_J.Med.Chem_49_4425
PubMedID: 16821801

Title : A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization - Hurst_2005_J.Neurosci_25_4396
Author(s) : Hurst RS , Hajos M , Raggenbass M , Wall TM , Higdon NR , Lawson JA , Rutherford-Root KL , Berkenpas MB , Hoffmann WE , Piotrowski DW , Groppi VE , Allaman G , Ogier R , Bertrand S , Bertrand D , Arneric SP
Ref : Journal of Neuroscience , 25 :4396 , 2005
Abstract : Several lines of evidence suggest a link between the alpha7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the alpha7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human alpha7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by alpha4beta2, alpha3beta4, and alpha9alpha10 nAChRs. PNU-120596 increased the channel mean open time of alpha7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of alpha7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances alpha7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.
ESTHER : Hurst_2005_J.Neurosci_25_4396
PubMedSearch : Hurst_2005_J.Neurosci_25_4396
PubMedID: 15858066

Title : Discovery and structure-activity relationship of quinuclidine benzamides as agonists of alpha7 nicotinic acetylcholine receptors - Bodnar_2005_J.Med.Chem_48_905
Author(s) : Bodnar AL , Cortes-Burgos LA , Cook KK , Dinh DM , Groppi VE , Hajos M , Higdon NR , Hoffmann WE , Hurst RS , Myers JK , Rogers BN , Wall TM , Wolfe ML , Wong E
Ref : Journal of Medicinal Chemistry , 48 :905 , 2005
Abstract : A library of benzamides was tested for alpha7 nicotinic acetylcholine receptor (nAChR) agonist activity using a chimeric receptor in a functional, cell-based, high-throughput assay. From this library, quinuclidine benzamides were found to have alpha7 nAChR agonist activity. The SAR diverged from the activity of this compound class verses the 5-HT(3) receptor, a structural homologue of the alpha7 nAChR. PNU-282987, the most potent compound from this series, was also shown to open native alpha7 nAChRs in cultured rat neurons and to reverse an amphetamine-induced gating deficit in rats.
ESTHER : Bodnar_2005_J.Med.Chem_48_905
PubMedSearch : Bodnar_2005_J.Med.Chem_48_905
PubMedID: 15715459

Title : Nicotine inhibits firing activity of dorsal raphe 5-HT neurones in vivo - Engberg_2000_Naunyn.Schmiedebergs.Arch.Pharmacol_362_41
Author(s) : Engberg G , Erhardt S , Sharp T , Hajos M
Ref : Naunyn Schmiedebergs Arch Pharmacol , 362 :41 , 2000
Abstract : It is established that the brain monoaminergic systems are among the main targets of several dependence-inducing drugs, including nicotine. In the present study extracellular electrophysiological recordings were performed to investigate the effects of nicotine on dorsal raphe 5-HT neurones. Nicotine, administered systemically (50-400 microg/kg, i.v.) in chloral hydrate-anaesthetised rats, induced a transient inhibition of the majority of 5-HT neurones recorded (38 of 45). The inhibition was rapid in onset (about 30 s) and the firing rate returned to baseline within 1-3 min. No apparent tachyphylaxis was observed to this inhibitory effect. The centrally acting nicotine antagonist mecamylamine (4 mg/kg, i.v.), but not the peripherally acting nicotine antagonist chlorisondamine (0.3 mg/kg, i.v.) antagonised the nicotine-induced inhibition of 5-HT neurones. The inhibition of 5-HT neurones was also blocked with a selective 5-HT1A receptor antagonist (WAY 100635; 0.1 mg/kg, i.v.), indicating a possible involvement of somato-dendritic 5-HT1A receptors in the effect of nicotine. Interestingly, microiontophoretic application of nicotine into the dorsal raphe failed to inhibit 5-HT neurones, suggesting an indirect effect of nicotine on 5-HT neurones, possibly involving afferent pathways.
ESTHER : Engberg_2000_Naunyn.Schmiedebergs.Arch.Pharmacol_362_41
PubMedSearch : Engberg_2000_Naunyn.Schmiedebergs.Arch.Pharmacol_362_41
PubMedID: 10935531

Title : Differential actions of acetylcholinesterase on the soma and dendrites of dopaminergic substantia nigra neurons in vitro - Hajos_1992_Brain.Res_585_416
Author(s) : Hajos M , Greenfield SA
Ref : Brain Research , 585 :416 , 1992
Abstract : In the substantia nigra, acetylcholinesterase (AChE) has non-cholinergic action on dopaminergic neurons. The subset of neurons particularly sensitive to AChE are characterized by functionally active apical dendrites extending into the pars reticulata and generating a powerful calcium conductance. This study thus attempted to establish directly the importance of these dendrites regarding the action of AChE. Segregation of the pars compacta from the pars reticulata did not affect the AChE-induced hyperpolarization on this sub-set of dopaminergic neurons. However, the ionic basis of the hyperpolarization was related to the integrity of the neurons: AChE caused an opening of potassium channels in intact cells. On the other hand when the pars reticulata containing apical dendrites was removed, an action of AChE involving the closure of calcium/sodium channels was revealed. The results demonstrate that the net effect of AChE need not be related to any particular segment of the dopaminergic neurons, whereas the nature of the mechanism underlying that effect depends on the presence, or otherwise, of the apical dendrites.
ESTHER : Hajos_1992_Brain.Res_585_416
PubMedSearch : Hajos_1992_Brain.Res_585_416
PubMedID: 1511329