73 research outputs found
A Review of the Pharmacological Properties of 3,4-dihydro-2(1H)- quinolinones
No full textThe 3,4-dihydro-2(1H)-quinolinone moiety is present in a number of pharmacologically active compounds. These include FDA approved drugs such as cilostazol, carteolol and aripiprazole as well as numerous experimental compounds. Compounds containing the 3,4-dihydro-2(1H)-quinolinone moiety also exhibit a variety of activities in both the peripheral and central tissues, which includes phosphodiesterase inhibition, blocking of β-adrenergic receptors, antagonism of vasopressin receptors and interaction with serotonin and dopamine receptors. Based on its versatility in drug design and action, this paper reviews the pharmacological actions of compounds containing the 3,4-dihydro-2(1H)- quinolinone scaffold with emphasis being placed on the most important and significant members of each activity clas
Inhibition of monoamine oxidase by 3,4-dihydro-2(1H)-quinolinone derivatives
No full textIn the present study, a series of 3,4-dihydro-2(1H)-quinolinone derivatives were synthesized and evaluated
as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The 3,4-dihydro-2(1H)-
quinolinone derivatives are structurally related to a series of coumarin (1-benzopyran-2-one) derivatives
which have been reported to act as MAO-B inhibitors. The results document that the quinolinones are
highly potent and selective MAO-B inhibitors with most homologues exhibiting IC50 values in the nanomolar
range. The most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone,
exhibits an IC50 value of 2.9 nM with a 2750-fold selectivity for MAO-B over the MAO-A isoform. An analysis
of the structure–activity relationships for MAO-B inhibition shows that substitution on the C7 position
of the 3,4-dihydro-2(1H)-quinolinone scaffold leads to significantly more potent inhibition
compared to substitution on C6. In this regard, a benzyloxy substituent on C7 is more favourable than
phenylethoxy and phenylpropoxy substitution on this position. It may be concluded that C7-substituted
3,4-dihydro-2(1H)-quinolinones are promising leads for the therapy of Parkinson’s disease
C6- and C7-substituted 3,4-dihydro-2(1H)-quinolinones as inhibitors of monoamine oxidase
No full textPurpose Monoamine oxidase (MAO) inhibitors are considered to be useful therapeutic agents and isoform specific inhibitors are employed for the treatment of depression and Parkinson’s disease. MAO inhibitors are also under investigation for the treatment of disorders ranging from Alzheimer’s disease, prostate cancer and certain cardiomyopathies. While a number of irreversible MAO inhibitors are available in the clinic, reversible inhibitors, particularly of the MAO-B isoform are still being developed. Based on our interest in discovering reversible inhibitors with specificity for MAO-B, we have recently reported that, among a series of 10 3,4-dihydro-2(1H)-quinolinone derivatives, are high potency MAO-B inhibitors, with a number of homologues displaying good selectivities for MAO-B over the MAO-A isoform.
Methods and Findings: To expand on these promising findings and to derive structure-activity relationships, the current study synthesizes a series of 14 3,4-dihydro-2(1H)-quinolinone derivatives. An evaluation of their MAO inhibition properties shows that all derivatives are MAO-B specific with the most potent inhibitor (3a) displaying an IC50 value of 0.0014 µM. Selectivities for MAO-B ranged from 99 to 40 000-fold.
Conclusions: It may thus be concluded that substitution of 3,4-dihydro-2(1H)-quinolinone on C6 and C7 with a variety of side chains yields highly potent and selective MAO-B inhibitors, compounds with existing and prospective therapeutic application
Life Changing Insights with Award Winning Celebrities
No full textLife Changing Insights with Dr. Alan Simberg and his guest Jeff Rasley & Dr. Letitia Wright
Jeff Rasley is the author of seven books and has published numerous articles in academic and mainstream periodicals, including Newsweek, Chicago Magazine, ABA Journal, Family Law Review, American Athenaeum, Pacific Magazine, Indy\u27s Child, The Journal of Communal Societies, The Chrysalis Reader, Faith & Fitness Magazine, Friends Journal, and Real Travel Adventures International Magazine. He is an award-winning photographer and his pictures taken in the Himalayas and Caribbean and Pacific islands have been published in several journals.http://www.jeffreyrasley.com/
Dr. Letitia S. Wright, D.C, is a celebrity, international speaker, talk show host, author, director and movie producer. As the host of the Wright Place TM TV Show, now in it’s 14th season with over 382 shows previously broadcast on television to over 6.5 million homes each week in Southern California on Direct TV Channel 64. Her interviews with the top Crowdfunding CEOs give her the insight needed to make crowdfunding easy for regular entrepreneurs, authors and entertainers. Dr. Wright has been the emcee for several crowdfunding events over the last 3 years and is a frequently sought after speaker and panelist. She is the author of the upcoming book 101 Tips to Successful Crowdfunding: From Someone Who’s Been There, Done That and Got the Cash. http://wrightplacetv.com/dr-wright
Monoamine oxidase inhibition properties of quinolinone analogues
No full textPhD (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2017Parkinson's disease (PD) is an age-related neurodegenerative disorder characterised by
selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the
brain. This leads to the loss of dopamine from the striatum, which is responsible for the motor
symptoms of PD. Monoamine oxidase (MAO) plays an important role in the
neurodegenerative processes and therapy of PD since dopamine is oxidised by MAO in the
basal ganglia. Inhibitors, of the MAO-B isoform conserve the depleted supply of dopamine
and are thus used in the therapy of PD. MAO-B inhibitors may also enhance the therapeutic
efficacy of L-dopa, the metabolic precursor of dopamine, by enhancing dopamine levels
derived from administered L-dopa.
In this study, three chemical classes were synthesised and evaluated as potential recombinant
human MAO-A and MAO-B inhibitors. These include (1) C6- and C7-substituted 3,4-
dihydro-2(1H)-quinolinones, (2) 2-phenoxyethoxy-substituted tetralones and (3) Npropargylamine-
2-aminotetralin (2-PAT). The quinolinone and tetralone derivatives are
structurally related to chemical classes that have been reported to inhibit the MAO enzymes,
including a-tetralone, 1-indanone and 3-coumaranone derivatives. 2-PAT is structurally
similar to rasagiline, an irreversible MAO-B inhibitor currently used in clinic.
C6- and C7-substituted 3,4-dihydro-2(1H)-quinolinone and 2-phenoxyethoxy tetralone
derivatives were synthesised by reacting 6- or 7-hydroxy-3,4-dihydro-2(1H)-quinolinone and
6- or 7-hydroxytetralone, respectively, with an appropriately substituted alkyl bromide in the
presence of base. 2-PAT was synthesised in low yield by dehydrating ~-tetralone and
propargylamine (commercially available) in the presence of sodium cyanoborohydride
(NaCNBH4).
To evaluate the MAO inhibitory properties (IC50 values) of the synthesised derivatives the
recombinant human MAO-A and MAO-B enzymes were used. The reversibility of inhibition
of selected derivatives was examined by employing dialysis, while the mode of MAO
inhibition was determined by constructing Lineweaver-Burk plots. To determine possible binding modes and key interactions of selected inhibitors with the
MAO enzymes, the inhibitors were docked into the MAO active sites.
The results document that the 3,4-dihydro-2(1H)-quinolinone derivatives are highly potent
and selective MAO-B inhibitors with the most potent inhibitor displaying an IC50 value of
0.0014 μM. Based on dialysis experiments it was concluded that a selected quinolinone
derivative is a reversible MAO-B inhibitor. The Lineweaver-Burk plots constructed for the
inhibition of MAO-B by the selected quinolinone derivative were linear and intersected on
the y-axis. These data indicated that this compound is a competitive MAO-B inhibitor with a
Ki value of 2.8 nM.
The results further document that 7-(2-phenoxyethoxy)-3,4-dihydronaphthalen-2(1H)-one
from the second series is a highly potent MAO-B inhibitor with an IC50 value of 0.033 μM.
Based on dialysis experiments it was concluded that this ~-tetralone derivative is a reversible
and competitive MAO-B inhibitor. An analysis of the Lineweaver-Burk plots indicated that
this compound inhibit MAO-B with a Ki value of 0.128 μM. This is the first report of the
MAO inhibition properties of a ~-tetralone.
Finally, 2-PAT was found to be a reversible MAO-A (IC5o= 0.721μM) inhibitor, while acting
as an inactivator of MAO-B (IC50 = 14.6 μM). 2-PAT is also approximately fivefold more
potent than toloxatone (IC50 = 3.92 μM), a clinically used antidepressant and reversible
MAO-A inhibitor.
It may thus be concluded that the synthesised compounds are promising potent MAO-B
inhibitors, and thus leads for the design of therapeutic agents for PDNational Research Foundation (NRF)Doctora
Monoamine oxidase inhibition by novel quinolinones
No full textMSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014Parkinson’s disease (PD) is an age-related neurodegenerative disorder. The degeneration of the neurons of the substantia nigra in the midbrain leads to the loss of dopamine from the striatum, which
is responsible for the motor symptoms of PD. In the brain, the enzyme, monoamine oxidase B (MAOB), An analysis of the Lineweaver-Burk plots indicated that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-
quinolinone inhibits MAO-B with a Ki value of 2.7 nM. An analysis of the structure-activity
relationships for MAO-B inhibition shows that substitution on the C7 position of the 3,4-dihydro-2(1H)-quinolinone moiety leads to significantly more potent inhibition compared to substitution on C6. In this regard, a benzyloxy substituent on C7 is more favourable than phenylethoxy and
phenylpropoxy substitution on this position.
In spite of this, C6-substituted 3,4-dihydro-2(1H)-quinolinone with potent MAO-B inhibitory activities were also identified. An analyses of selected properties of the 3,4-dihydro-2(1H)-quinolinones showed that the compounds are highly lipophilic with logP values in the range of 3.03-4.55. LogP values between 1 and 3 are, however, in the ideal range for bioavailability. The compounds synthesised have logP values higher than 3, which may lead to lower bioavailability.
Laboratory data further showed that none of the 3,4-dihydro-2(1H)-quinolinones are highly toxic to cultured cells at the concentrations, 1 μM and 10 μM, tested. For example, the most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, reduced cell viability to 88.11% and 86.10% at concentrations of 1 μM and 10 μM, respectively. These concentrations are well above its IC50 value for the inhibition of MAO-B. At concentrations required for MAO-B inhibition, the more potent 3,4-dihydro-2(1H)-quinolinones are thus unlikely to be cytotoxic. It may thus be concluded that C7-substituted 3,4-dihydro-2(1H)-quinolinones are promising highly
potent and selective MAO-B inhibitors, and thus leads for the therapy of Parkinson’s disease. represents a major catabolic pathway of dopamine. Inhibitors of MAO-B conserve the depleted supply of dopamine and are thus used in the therapy of PD. In the present study, a series of 3,4-dihydro-2(1H)-quinolinone derivatives were synthesized and evaluated as inhibitors of recombinant human MAO-A and MAO-B. These quinolinone derivatives are structurally related to a series of coumarin (1-benzopyran-2-one) derivatives, which has been reported to act as MAO-B inhibitors. C6-and C7-substituted 3,4-dihydro-2(1H)-quinolinone derivatives were synthesized by reacting 6- or 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with an appropriately substituted alkyl bromide in the presence of base. To evaluate the MAO inhibitory properties (IC50 values) of the quinolinone
derivatives the recombinant human MAO-A and MAO-B enzymes were used. The reversibility of inhibition of a representative 3,4-dihydro-2(1H)-quinolinone derivative was examined by measuring the recovery of enzyme activity after the dilution of the enzyme-inhibitor complexes, while the mode
of MAO inhibition was determined by constructing Lineweaver-Burk plots. To determine the lipophilicity of the 3,4-dihydro-2(1H)-quinolinone derivatives, the logP values were measured. The toxicity of the 3,4-dihydro-2(1H)-quinolinone derivatives towards cultured cells (cytotoxicity) was also measured. The results document that the 3,4-dihydro-2(1H)-quinolinone derivatives are highly potent and selective MAO-B inhibitors with most homologues exhibiting IC50 values in the nanomolar range. The most potent MAO-B inhibitor, 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone, exhibits an IC50 value of 2.9 nM with a 2750-fold selectivity for MAO-B over the MAO-A isoform. As a MAO-B inhibitor, this compound is approximately equipotent to the most potent coumarin derivative (IC50 = 1.14 nM) reported in literature. Since MAO-B activity could be recovered after dilution of enzyme-inhibitor mixtures, it may be concluded that 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-
quinolinone is a reversible MAO-B inhibitor. The Lineweaver-Burk plots constructed for the inhibition of MAO-B by 7-(3-bromobenzyloxy)-3,4-dihydro-2(1H)-quinolinone were linear and intersected on the y-axis. These data indicated that this compound also is a competitive MAO-B
inhibitor.Master
Switching circuit energy balance in iLabs on experimental lab server architecture
No full textThesis: M. Eng., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2015.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 121-122).In Electrical Engineering courses, it is important that students have hands-on experience with a circuit and components to witness their behavior and compare it with theoretical models. The MIT iLab Project develops online laboratories that allow students to perform experiments through a web browser from anywhere in the world. One such lab used in the Introduction to Circuits class, the NMOS Resistor Amplifier Lab, allows students to analyze the switching waveforms of a transistor. This thesis describes the integration of a thermal camera to the NMOS-Resistor Amplifier Lab to educate students about energy dissipation. The first version of this lab, built entirely in LabVIEW, on iLabs' existing Shared Architecture could not support an interactive lightweight client. In response, the Experimental Lab Server Architecture (ELSA) was developed as a new interface connecting an experiment, client, and Service Broker. In the first prototype of the Thermal Lab in ELSA, a Java Applet Client uses REST calls to send commands and acquire data from the LabVIEW experiment running on the server.by Letitia Weixia Li.M. Eng
A comparative study of nursery school feeding at Lane College and Spelman College with proposals for improved nursery school feeding at Lane College, 1948
No full textThe fuzzy theory and women writers in the late eighteenth century
No full text'Fuzzy Theory and Women Writers in the Late Eighteenth Century' contends
that women writers require more careful critical treatment, and suggests that critics
are still bound by the outdated logic of the Law of the Excluded Middle. This law,
first formulated by Aristotle, and developed by Gottfried Leibniz in the early
eighteenth century, indicates that where there are two contradictory prepositions, one
must be true and the other false; a female writer must, therefore, either be feminine or
masculine, conservative or radical. The twentieth century concept of Fuzzy logic,
however, helped mathematicians and engineers to manage reasoning that was only
approximate, rather than exact. Borrowing from this, the thesis will employ the
Fuzzy Set Theory, which permits the gradual assessment of elements in a set, rather
than relying on elements that are assessed in binaric terms (the principle of bivalence,
or, contradiction). Put simply, the Fuzzy Set Theory does away with binaries, the Law
of the Excluded Middle, and the Law of Contradiction, allowing subjects to be
imprecise, and changeable. Thus, each chapter will construct a Fuzzy Set by which a
variety of eighteenth century debates, with which women writers engaged, can be
examined. The thesis will show that all such concepts are subjective and unstable—
changeable and open to personal interpretation, and will discuss such writers as Mary
Wollstonecraft, Catherine Macaulay, Charlotte Smith, Anna Letitia Barbauld, Mary
Hays, Lucy Aikin, Hannah More and Joanna Southcott
Identity, anxiety, and ambiguity within the eighteenth-century representation of the slave: Anna Letitia Barbauld, Hannah More, and Phillis Wheatley
No full textEighteenth-century poets, Anna Letitia Barbauld, Hannah More, and Phillis Wheatley represented the slave, contributing to the creation of an African identity that both challenged and affirmed the cultural perception of the African, the Other. I examined the poetry using the New Historical, Feminist, and Post-Colonial perspectives and considered the ways in which social assumptions and historical events influenced the writers in their representations of the African slave. Examining the poets' representations of the African slave allowed me to explore the act of representation and focus upon the contradictory assumptions and images that are involved with representation and its connection to the creation of identity. To understand the poets' representations of the African, it was necessary to consider their work within its historical context, particularly the eighteenth-century perceptions of ' race,' the African, and the abolitionist cause. Abolitionists attempted to create an alternative image of the African that focused upon shared human bonds and produced sympathy for the plight of the African. Barbauld's and More's poetry were written in an effort to create a sympathetic image of the African to convince the politicians to abolish Britain's participation in the slave trade; however, while speaking out against the slave trade, the two British poets created contradictory images and implied that the African belonged to an inferior ' race.' As an African native, Wheatley provides a contrast to Barbauld and More and their representations of the African which indicates that the voice of the Other is susceptible to contradictions, social assumptions, and conflicting images in the representation of the Other. Ultimately, the three women's poetry provides a case study by which to examine the conflicts and contradictions that are a part of the process of literary representation and the ways in which representation contributes to a conflicted identity.The original print copy of this thesis may be available here: http://wizard.unbc.ca/record=b119730
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