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Dive into the research topics where Jane R. Hanrahan is active.

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Featured researches published by Jane R. Hanrahan.


British Journal of Pharmacology | 2011

Flavonoid modulation of GABAA receptors

Jane R. Hanrahan; Mary Chebib; Graham A. R. Johnston

There has been a resurgence of interest in synthetic and plant‐derived flavonoids as modulators of γ‐amino butyric acid‐A (GABAA) receptor function influencing inhibition mediated by the major inhibitory neurotransmitter GABA in the brain. Areas of interest include (i) flavonoids that show subtype selectivity in recombinant receptor studies in vitro consistent with their behavioural effects in vivo, (ii) flumazenil‐insensitive modulation of GABAA receptor function by flavonoids, (iii) the ability of some flavonoids to act as second‐order modulators of first‐order modulation by benzodiazepines and (iv) the identification of the different sites of action of flavonoids on GABAA receptor complexes. An emerging area of interest is the activation of GABAA receptors by flavonoids in the absence of GABA. The relatively rigid shape of flavonoids means that they are useful scaffolds for the design of new therapeutic agents. Like steroids, flavonoids have wide‐ranging effects on numerous biological targets. The challenge is to understand the structural determinants of flavonoid effects on particular targets and to develop agents specific for these targets.


Current Drug Targets - Cns & Neurological Disorders | 2003

GABAC Receptors as Drug Targets

Graham A. R. Johnston; Mary Chebib; Jane R. Hanrahan; Kenneth N. Mewett

GABA(C) receptors are the least studied of the three major classes of GABA receptors. The physiological roles of GABA(C) receptors are still being unravelled and the pharmacology of these receptors is being developed. A range of agents has been described that act on GABA(C) receptors with varying degrees of specificity as agonists, partial agonists, antagonists and allosteric modulators. Pharmacological differences are known to exist between subtypes of cloned GABA(C) receptors that have been cloned from mammalian sources. There is evidence for functional GABA(C) receptors in the retina, spinal cord, superior colliculus, pituitary and gastrointestinal tract. Given the lower abundance and less widespread distribution of GABA(C) receptors in the CNS compared to GABA(A) receptors, GABA(C) receptors may be a more selective drug target than GABA(A) receptors. The major indications for drugs acting on GABA(C) receptors are in the treatment of visual, sleep and cognitive disorders. The most promising leads are THIP, a GABA(C) receptor antagonist in addition to its well known activity as a GABA(A) receptor partial agonist, which is being evaluated for sleep therapy, and CGP36742, an orally active GABA(B) and GABA(C) receptor antagonist, which enhances cognition. Analogues of THIP and CGP36742, such as aza-THIP, that are selective for GABA(C) receptors are being developed. TPMPA and related compounds such as P4MPA, PPA and SEPI are also important leads for the development of systemically active selective GABA(C) receptor antagonists.


Journal of Pharmacology and Experimental Therapeutics | 2009

Novel, Potent, and Selective GABAC Antagonists Inhibit Myopia Development and Facilitate Learning and Memory

Mary Chebib; Tina Hinton; Katrina L. Schmid; Darren R. Brinkworth; H. Qian; Susana Matos; Hye-Lim Kim; Heba Abdel-Halim; Rohan J. Kumar; Graham A. R. Johnston; Jane R. Hanrahan

This study reports pharmacological and physiological effects of cis- and trans-(3-aminocyclopentanyl)butylphosphinic acid (cis- and trans-3-ACPBPA). These compounds are conformationally restricted analogs of the orally active GABAB/C receptor antagonist (3-aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742). cis-[IC50(ρ1) = 5.06 μM and IC50(ρ2) = 11.08 μM; n = 4] and trans-3-ACPMPA [IC50(ρ1) = 72.58 μM and IC50(ρ2) = 189.7 μM; n = 4] seem competitive at GABAC receptors expressed in Xenopus laevis oocytes, having no effect as agonists (1 mM) but exerting weak antagonist (1 mM) effects on human GABAA and GABAB receptors. cis-3-ACPBPA was more potent and selective than the trans-compound, being more than 100 times more potent at GABAC than GABAA or GABAB receptors. cis-3-ACPBPA was further evaluated on dissociated rat retinal bipolar cells and dose-dependently inhibited the native GABAC receptor (IC50 = 47 ± 4.5 μM; n = 6). When applied to the eye as intravitreal injections, cis- and trans-3-ACPBPA prevented experimental myopia development and inhibited the associated vitreous chamber elongation, in a dose-dependent manner in the chick model. Doses only 10 times greater than required to inhibit recombinant GABAC receptors caused the antimyopia effects. Using intraperitoneal administration, cis- (30 mg/kg) and trans-3-ACPBPA (100 mg/kg) enhanced learning and memory in male Wistar rats; compared with vehicle there was a significant reduction in time for rats to find the platform in the Morris water maze task (p < 0.05; n = 10). As the physiological effects of cis- and trans-3-ACPBPA are similar to those reported for CGP36742, the memory and refractive effects of CGP36742 may be due in part to its GABAC activity.


Advances in pharmacology (San Diego) | 2006

Modulation of Ionotropic GABA Receptors by Natural Products of Plant Origin

Graham A. R. Johnston; Jane R. Hanrahan; Mary Chebib; Rujee K. Duke; Kenneth N. Mewett

Publisher Summary This chapter discusses the modulation of ionotropic γ‐aminobutyric acid (GABA) receptors by natural products of plant origin. There is an impressive array of natural products that are known to influence the function of ionotropic receptors for GABA, the major inhibitory neurotransmitter in the brain. The major chemical classes of such natural products are flavonoids, terpenoids, phenols, and polyacetylenic alcohols. The interaction of flavonoids with benzodiazepine modulatory sites on GABAA receptors lead to the great interest in flavonoids as positive modulators of such receptors, many of the interactions between flavonoids and GABAA receptors do not involve classical flumazenil‐sensitive benzodiazepine sites. There are significant synergistic interactions between some of these positive modulators such as between substances isolated from Valeriana officinalis. Thus, the sleep inducing effects of hesperidin are potentiated by 6‐methylapigenin, while the sedating and sleep inducing effects of valerenic acid are potentiated when co‐administered with the flavonoid glycoside linarin. The discovery of second order positive modulators adds new dimension to the concept of the allosteric modulation of GABAA receptors. Second order positive modulators act only in conjunction with a specific first order positive modulator.


Bioorganic & Medicinal Chemistry Letters | 2003

Semisynthetic preparation of amentoflavone: A negative modulator at GABAA receptors

Jane R. Hanrahan; Mary Chebib; Neil L.M. Davucheron; Belinda J. Hall; Graham A. R. Johnston

Amentoflavone is found in a number of plants with medicinal properties, including Ginkgo biloba and Hypericum perforatum (St. Johns Wort). We have developed a rapid and economic semi-synthetic preparation of amentoflavone from biflavones isolated from autumnal Ginkgo biloba leaves. Several studies have shown that amentoflavone binds to benzodiazepine receptors. Using two electrode voltage-clamp methodology, amentoflavone has been shown to be a negative modulator of GABA at GABA(A) alpha(1)beta(2)gamma(2L) receptors expressed in Xenopus laevis oocytes This action appears to be independent of the flumazenil-sensitive benzodiazepine modulatory sites on the GABA(A) receptor.


Chemical Biology & Drug Design | 2008

A Molecular Basis for Agonist and Antagonist Actions at GABA C Receptors

Heba Abdel-Halim; Jane R. Hanrahan; David E. Hibbs; Graham A. R. Johnston; Mary Chebib

We modelled the N‐terminal ligand‐binding domain of the ρ1 GABAC receptor based on the Lymnaea stagnalis acetylcholine‐binding protein (L‐AChBP) crystal structure using comparative modelling and validated using flexible docking guided by known mutagenesis studies. A range of known ρ1 GABAC receptor ligands comprising seven full agonists, 10 partial agonists, 43 antagonists and 12 inactive molecules were used to evaluate and validate the models. Of the 50 models identified, six models that allowed flexible ligand docking in accordance with the experimental data were selected and used to study detailed receptor‐ligand interactions. The most refined model to accommodate all known active ligands featured a cavity comprising of a volume of 488 Å3. A detailed analysis of the interaction between the ρ1 GABAC receptor model and the docked ligands revealed possible H‐bonds and cation‐π interactions between the different ligands and binding site residues. Based on quantum mechanical/molecular mechanical (QM/MM) calculations, the model showed distinctive conformations of loop C that provided a molecular basis for agonist and antagonist actions. Agonists elicit loop C closure, while a more open loop C was observed upon antagonist binding. The model differentiates the role for key residues known to be involved in either binding and/or gating.


British Journal of Pharmacology | 2012

2'-Methoxy-6-methylflavone: A novel anxiolytic and sedative with subtype selective activating and modulating actions at GABA A receptors

Nasiara Karim; John Curmi; Navnath Gavande; Graham A. R. Johnston; Jane R. Hanrahan; M. Louise Tierney; Mary Chebib

BACKGROUND AND PURPOSE Flavonoids are known to have anxiolytic and sedative effects mediated via actions on ionotropic GABA receptors. We sought to investigate this further.


British Journal of Pharmacology | 2011

Naringin directly activates inwardly rectifying potassium channels at an overlapping binding site to tertiapin-Q.

Tin T. Yow; Elena Pera; Nathan Absalom; Marika Heblinski; Graham A. R. Johnston; Jane R. Hanrahan; Mary Chebib

BACKGROUND G protein‐coupled inwardly rectifying potassium (KIR3) channels are important proteins that regulate numerous physiological processes including excitatory responses in the CNS and the control of heart rate. Flavonoids have been shown to have significant health benefits and are a diverse source of compounds for identifying agents with novel mechanisms of action.


Journal of Medicinal Chemistry | 2008

Novel gamma-aminobutyric acid rho1 receptor antagonists; synthesis, pharmacological activity and structure-activity relationships.

Rohan J. Kumar; Mary Chebib; David E. Hibbs; Hye-Lim Kim; Graham A. R. Johnston; Noeris K. Salam; Jane R. Hanrahan

Gamma-aminobutyric acid (GABA) analogues based on 4-amino-cyclopent-1-enyl phosphinic acid ( 34- 42) and 3-aminocyclobutane phosphinic acids ( 51, 52, 56, 57) were investigated in order to obtain selective homomeric rho 1 GABA C receptor antagonists. The effect of the stereochemistry and phosphinic acid substituent of these compounds on potency and selectivity within the GABA receptor subtypes was investigated. Compounds of high potency at GABA C rho 1 receptors ( 36, K B = 0.78 microM) and selectivity greater than 100 times ( 41, K B = 4.97 microM) were obtained. The data obtained was analyzed along with the known set of GABA C rho 1 receptor-ligands, leading to the development of a pharmacophore model for this receptor, which can be used for in silico screening.


PLOS ONE | 2014

GABAA Receptors Containing ρ1 Subunits Contribute to In Vivo Effects of Ethanol in Mice

Yuri A. Blednov; Jillian M. Benavidez; Mendy Black; Courtney Leiter; Elizabeth Osterndorff-Kahanek; David G. Johnson; Cecilia M. Borghese; Jane R. Hanrahan; Graham A. R. Johnston; Mary Chebib; R. Adron Harris

GABAA receptors consisting of ρ1, ρ2, or ρ3 subunits in homo- or hetero-pentamers have been studied mainly in retina but are detected in many brain regions. Receptors formed from ρ1 are inhibited by low ethanol concentrations, and family-based association analyses have linked ρ subunit genes with alcohol dependence. We determined if genetic deletion of ρ1 in mice altered in vivo ethanol effects. Null mutant male mice showed reduced ethanol consumption and preference in a two-bottle choice test with no differences in preference for saccharin or quinine. Null mutant mice of both sexes demonstrated longer duration of ethanol-induced loss of righting reflex (LORR), and males were more sensitive to ethanol-induced motor sedation. In contrast, ρ1 null mice showed faster recovery from acute motor incoordination produced by ethanol. Null mutant females were less sensitive to ethanol-induced development of conditioned taste aversion. Measurement of mRNA levels in cerebellum showed that deletion of ρ1 did not change expression of ρ2, α2, or α6 GABAA receptor subunits. (S)-4-amino-cyclopent-1-enyl butylphosphinic acid (“ρ1” antagonist), when administered to wild type mice, mimicked the changes that ethanol induced in ρ1 null mice (LORR and rotarod tests), but the ρ1 antagonist did not produce these effects in ρ1 null mice. In contrast, (R)-4-amino-cyclopent-1-enyl butylphosphinic acid (“ρ2” antagonist) did not change ethanol actions in wild type but produced effects in mice lacking ρ1 that were opposite of the effects of deleting (or inhibiting) ρ1. These results suggest that ρ1 has a predominant role in two in vivo effects of ethanol, and a role for ρ2 may be revealed when ρ1 is deleted. We also found that ethanol produces similar inhibition of function of recombinant ρ1 and ρ2 receptors. These data indicate that ethanol action on GABAA receptors containing ρ1/ρ2 subunits may be important for specific effects of ethanol in vivo.

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