%0 Journal Article
%~ PubMed
%A Karim, Nasiara
%A Curmi, John
%A Gavande, Navnath
%A Johnston, Graham A R
%A Hanrahan, Jane R
%A Tierney, M Louise
%A Chebib, Mary
%T 2'-Methoxy-6-methylflavone: A novel anxiolytic and sedative with subtype selective activating and modulating actions at GABA(A) receptors.
%B British journal of pharmacology
%D 2012
%C United Kingdom
%I John Wiley & Sons Ltd.
%V 165
%N 4
%P 880-96
%@ 0007-1188
%X Flavonoids are known to have anxiolytic and sedative effects mediated via actions on ionotropic GABA receptors. We sought to investigate this further.
%Z FOR Codes: 111501 111504


%0 Journal Article
%~ PubMed
%A Thompson, Andrew J
%A McGonigle, Ian
%A Duke, Rujee
%A Johnston, Graham A R
%A Lummis, Sarah C R
%T A single amino acid determines the toxicity of Ginkgo biloba extracts.
%B The FASEB Journal
%D 2012
%C United States
%I Federation of American Societies for Experimental
%V 26
%N 5
%P 1884-1891
%@ 1530-6860
%X Ginkgo biloba extracts are currently used for a wide range of health-related conditions. Some of the medical benefits of these extracts are controversial, but their lack of toxicity in humans is not in doubt. These extracts are, however, highly toxic to insects. Their active components (ginkgolides and bilobalide) have structures similar to the convulsant picrotoxin, a GABA(A) receptor antagonist, so their lack of toxicity in mammals is puzzling. Here, we show that the different compositions of insect and vertebrate GABA receptor pores are responsible for the differing toxicities. Insect GABA receptors contain Ala at their 2'' position in the pore. Substitution with Val, which is the equivalent residue in vertebrate GABA(A) receptor ?-subunits, decreases ginkgolide potency by up to 10,000-fold. The reverse mutation in vertebrate GABA(A) ?1 subunits increased the sensitivity of ?1?2 and ?1?2?2 receptors to ginkgolides. Mutant cycle analysis demonstrates a strong interaction between the ginkgolides and the 2'' residue, a result supported by in silico docking of compounds into a model of the pore. We conclude that the insecticidal activity of G. biloba extracts can be attributed to their effects at insect GABA receptors, and the presence of a Val at the 2'' position in vertebrate GABA(A) receptors explains why these compounds are not similarly toxic to humans.-Thompson, A. J., McGonigle, I., Duke, R., Johnston, G. A. R., Lummis, S. C. R. A single amino acid determines the toxicity of Ginkgo biloba extracts.
%Z FOR Codes: 110101 110499 110101 111501


%0 Journal Article
%~ PubMed
%A Yamamoto, Izumi
%A Absalom, Nathan
%A Carland, Jane E
%A Doddareddy, Munikumar R
%A Gavande, Navnath
%A Johnston, Graham A R
%A Hanrahan, Jane R
%A Chebib, Mary
%T Differentiating Enantioselective Actions of GABOB: A Possible Role for Threonine 244 in the Binding Site of GABA(C) ρ(1) Receptors.
%B ACS Chemical Neuroscience
%D 2012
%C United States
%I American Chemical Society
%V 3
%N 9
%P 665-673
%@ 1948-7193
%X 
%Z FOR Codes: 30401 111501


%0 Journal Article
%~ PubMed
%A Fernandez, Sebastian P
%A Karim, Nasiara
%A Mewett, Kenneth N
%A Chebib, Mary
%A Johnston, Graham Ar
%A Hanrahan, Jane R
%T Flavan-3-ol esters: new agents for exploring modulatory sites on GABA(A) receptors.
%B British Journal of Pharmacology
%D 2012
%C United Kingdom
%I John Wiley & Sons Ltd.
%V 165
%N 4
%P 965-977
%@ 0007-1188
%X Background and purpose:??? Enhancement of GABAergic function is the primary mechanism of important therapeutic agents such as benzodiazepines, barbiturates, neurosteroids, general anesthetics and some anticonvulsants. Despite their chemical diversity, many studies have postulated that these agents may bind at a common or overlapping binding site, or share an activation domain. Similarly, we previously reported the action of flavan-3-ol esters as positive modulators of GABA(A) receptors, and noted that this action resembled the in vitro profile of general anesthetics. In this study we further investigate interactions between these agents. Experimental approach:??? Using two-electrode voltage clamp electrophysiological recordings on receptors of known subunit composition expressed in Xenopus oocytes we evaluated positive modulation by etomidate, loreclezole, diazepam, thiopentone, 5??-pregnan-3??-ol-20-one and the flavan-3-ol ester Fa131 on wild-type and mutated GABA(A) receptors. Key results:??? We report a new flavan Fa173, which neutralises the potentiating actions of Fa131, etomidate and loreclezole at ??1??2 and ??1??2??2L GABA(A) receptors. Furthermore potentiation of high, but not low, concentrations of diazepam can be blocked by Fa173. However Fa173 did not block the potentiation induced by propofol, the neurosteroid 5??-pregnan-3??-ol-20-one (THP) or the barbiturate thiopental. Mutational studies on "anesthetic-influencing" residues showed that ??1M236W??2??2L and ??1??2N265S??2L receptors were resistant to potentiation by etomidate, loreclezole and Fa131, compared to wild-type GABA(A) receptors. Conclusions and implications:??? This evidence suggests that flavan-3-ol derivatives are ligands which interact with an overlapping binding site or activation domain as etomidate and loreclezole on GABA(A) receptors. Furthermore, the low-affinity effects of diazepam are mediated via the same site.
%Z FOR Codes: 111501 30401


%0 Journal Article
%~ PubMed
%A Karim, Nasiara
%A Wellendorph, Petrine
%A Absalom, Nathan
%A Bang, Line Haunstrup
%A Jensen, Marianne Lerbech
%A Hansen, Maja Michelle
%A Lee, Ho Joon
%A Johnston, Graham A R
%A Hanrahan, Jane R
%A Chebib, Mary
%T Low nanomolar GABA effects at extrasynaptic α4β1/β3δ GABA(A) receptor subtypes indicate a different binding mode for GABA at these receptors.
%B Biochemical Pharmacology
%D 2012
%C United States
%I Elsevier Inc.
%V 84
%N 4
%P 549-557
%@ 1873-2968
%X Ionotropic GABA(A) receptors are a highly heterogenous population of receptors assembled from a combination of multiple subunits. The aims of this study were to characterize the potency of GABA at human recombinant ??-containing extrasynaptic GABA(A) receptors expressed in Xenopus oocytes using the two-electrode voltage clamp technique, and to investigate, using site-directed mutagenesis, the molecular determinants for GABA potency at ??4??3?? GABA(A) receptors. ??4/??-Containing GABA(A) receptors displayed high sensitivity to GABA, with mid-nanomolar concentrations activating ??4??1?? (EC(50)=24nM) and ??4??3?? (EC(50)=12nM) receptors. In the majority of oocytes expressing ??4??3?? subtypes, GABA produced a biphasic concentration-response curve, and activated the receptor with low and high concentrations (EC(50)(1)=16nM; EC(50)(2)=1.2??M). At ??4??2??, GABA had low micromolar activity (EC(50)=1??M). An analysis of 10 N-terminal singly mutated ??4??3?? receptors shows that GABA interacts with amino acids different to those reported for ??1??2??2 GABA(A) receptors. Residues Y205 and R207 of the ??3-subunit significantly affected GABA potency, while the residue F71 of the ??4- and the residue Y97 of the ??3-subunit did not significantly affect GABA potency. Mutating the residue R218 of the ??-subunit, equivalent to the GABA binding residue R207 of the ??2-subunit, reduced the potency of GABA by 670-fold, suggesting a novel GABA binding site at the ??-subunit interface. Taken together, GABA may have different binding modes for extrasynaptic ??-containing GABA(A) receptors compared to their synaptic counterparts.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Huang, Shelley H
%A Lewis, Trevor G
%A Lummis, Sarah C R
%A Thompson, Andrew J
%A Chebib, Mary
%A Johnston, Graham A R
%A Duke, Rujee K
%T Mixed antagonistic effects of the ginkgolides at recombinant human ρ(1)GABA(C) receptors.
%B Neuropharmacology
%D 2012
%C United Kingdom
%I Pergamon
%V 63
%N 6
%P 1127-1139
%@ 0028-3908
%X The diterpene lactones of Ginkgo biloba, ginkgolides A, B and C are antagonists at a range of Cys-loop receptors. This study examined the effects of the ginkgolides at recombinant human ??(1) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp. The ginkgolides were moderately potent antagonists with IC(50)s in the ??M range. At 10????M, 30????M and 100????M, the ginkgolides caused rightward shifts of GABA dose-response curves and reduced maximal GABA responses, characteristic of noncompetitive antagonists, while the potencies showed a clear dependence on GABA concentration, indicating apparent competitive antagonism. This suggests that the ginkgolides exert a mixed-type antagonism at the ??(1) GABA(C) receptors. The ginkgolides did not exhibit any obvious use-dependent inhibition. Fitting of the data to a number of kinetic schemes suggests an allosteric inhibition as a possible mechanism of action of the ginkgolides which accounts for their inhibition of the responses without channel block or use-dependent inhibition. Kinetic modelling predicts that the ginkgolides exhibit saturation of antagonism at high concentrations of GABA, but this was only partially observed for ginkgolide B. It also suggests that there may be different binding sites in the closed and open states of the receptor, with a higher affinity for the receptor in the closed state.
%Z FOR Codes: 111501


%0 Journal Article
%A Yamamoto, Izumi
%A Carland, Jane
%A Locock, Katherine
%A Gavande, Navnath
%A Absalom, Nathan
%A Hanrahan, Jane
%A Allan, Robin
%A Johnston, Graham
%A Collins, Mary
%T Structurally Diverse GABA Antagonists Interact Differently with Open and Closed Conformational States of the ρ1 Receptor
%B ACS Chemical Neuroscience
%D 2012
%C United States
%I American Chemical Society
%V 3
%N 4
%P 293–301
%@ 1948-7193
%X 
%Z FOR Codes: 110902 111504


%0 Journal Article
%~ PubMed
%A Karim, Nasiara
%A Gavande, Navnath
%A Wellendorph, Petrine
%A Johnston, Graham A R
%A Hanrahan, Jane R
%A Chebib, Mary
%T 3-Hydroxy-2'-methoxy-6-methylflavone: A potent anxiolytic with a unique selectivity profile at GABA(A) receptor subtypes.
%B Biochemical pharmacology
%D 2011
%C United States
%I Elsevier Inc.
%V 82
%N 12
%P 1971-83
%@ 0006-2952
%X Genetic and pharmacological studies have demonstrated that ??2- and ??4-containing GABA(A) receptors mediate the anxiolytic effects of a number of agents. Flavonoids are a class of ligands that act at GABA(A) receptors and possess anxiolytic effects in vivo. Here we demonstrate that the synthetic flavonoid, 3-hydroxy-2''-methoxy-6-methylflavone (3-OH-2''MeO6MF) potentiates GABA-induced currents at recombinant ??1/2??2, ??1/2/4/6??1-3??2L but not ??3/5??1-3??2L receptors expressed in Xenopus oocytes. The enhancement was evident at micromolar concentrations (EC(50) values between 38 and 106 ??M) and occurred in a flumazenil-insensitive manner. 3-OH-2''MeO6MF displayed preference for ??2/3- over ??1-containing receptors with the highest efficacy observed at ??2??2/3??2L, displaying a 4-11-fold increase in efficacy over ??2??1??2L and ??1/4/6-containing subtypes. In contrast, 3-OH-2''MeO6MF acted as a potent bicuculline-sensitive activator, devoid of potentiation effects at extrasynaptic ??4??2/3?? receptors expressed in oocytes. The affinity of 3-OH-2''MeO6MF for ??4??2/3?? receptors (EC(50) values between 1.4 and 2.5 ??M) was 10-fold higher than at ??4??1?? GABA(A) receptors. 3-OH-2''MeO6MF acted as a full agonist at ??4??2/3?? (105% of the maximal GABA response) but as a partial agonist at ??4??1?? (61% of the maximum GABA response) receptors. In mice, 3-OH-2''MeO6MF (1-100 mg/kg i.p.) induced anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark paradigms. No sedative or myorelaxant effects were detected using holeboard, actimeter and horizontal wire tests and only weak barbiturate potentiating effects on the loss of righting reflex test. Taken together, these data suggest that 3-OH-2''MeO6MF is an anxiolytic without sedative and myorelaxant effects acting through positive allosteric modulation of the ??2??2/3??2L and direct activation of ??4??2/3?? GABA(A) receptor subtypes.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Yamamoto, Izumi
%A Deniau, Gildas P
%A Gavande, Navnath
%A Chebib, Mary
%A Johnston, Graham A R
%A O'Hagan, David
%T Agonist responses of (R)- and (S)-3-fluoro-??-aminobutyric acids suggest an enantiomeric fold for GABA binding to GABA(C) receptors.
%B Chemical communications (Cambridge, England)
%D 2011
%C United Kingdom
%I Royal Society of Chemistry
%V 47
%N 28
%P 7956-8
%@ 1364-548X
%X The enantiomers of 3F-GABA were evaluated on GABA(C) receptors. Both enantiomers were agonists, with the (R)-enantiomer being an order of magnitude more potent. This result is consistent with a folded binding mode for GABA, a conclusion which suggests a different binding mode to that found in the related but pharmacologically distinct GABA(A) receptors.
%Z FOR Codes: 30401 30402 111501


%0 Journal Article
%~ PubMed
%A Hanrahan, Jane R
%A Chebib, Mary
%A Johnston, Graham A R
%T Flavonoid modulation of GABA(A) receptors.
%B British Journal of Pharmacology
%D 2011
%C United Kingdom
%I John Wiley & Sons Ltd.
%V 163
%N 2
%P 234-245
%@ 0007-1188
%X There has been a resurgence of interest in synthetic and plant-derived flavonoids as modulators of ??-amino butyric acid-A (GABA(A) ) 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 GABA(A) 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 GABA(A) receptor complexes. An emerging area of interest is the activation of GABA(A) 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.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Thompson, Andrew J
%A Jarvis, Gavin E
%A Duke, Rujee K
%A Johnston, Graham A R
%A Lummis, Sarah C R
%T Ginkgolide B and bilobalide block the pore of the 5-HT?receptor at a location that overlaps the picrotoxin binding site.
%B Neuropharmacology
%D 2011
%C United Kingdom
%I Pergamon
%V 60
%N 2-3
%P 488-495
%@ 0028-3908
%X Extracts from the Ginkgo biloba tree are widely used as herbal medicines, and include bilobalide (BB) and ginkgolides A and B (GA and GB). Here we examine their effects on human 5-HT(3)A and 5-HT(3)AB receptors, and compare these to the effects of the structurally related compounds picrotin (PTN) and picrotoxinin (PXN), the two components of picrotoxin (PTX), a known channel blocker of 5-HT(3), nACh and GABA(A) receptors. The compounds inhibited 5-HT-induced responses of 5-HT(3) receptors expressed in Xenopus oocytes, with IC(50) values of 470 ?M (BB), 730 ?M (GB), 470 ?M (PTN), 11 ?M (PXN) and >1mM (GA) in 5-HT(3)A receptors, and 3.1mM (BB), 3.9 mM (GB), 2.7 mM (PTN), 62 ?M (PXN) and >1mM (GA) in 5-HT(3)AB receptors. Radioligand binding on receptors expressed in HEK 293 cells showed none of the compounds displaced the specific 5-HT(3) receptor antagonist [(3)H]granisetron, confirming that they do not act at the agonist binding site. Inhibition by GB at 5-HT(3)A receptors is weakly use-dependent, and recovery is activity dependent, indicating channel block. To further probe their site of action at 5-HT(3)A receptors, BB and GB were applied alone or in combination with PXN, and the results fitted to a mathematical model; the data revealed partially overlapping sites of action. We conclude that BB and GB block the channel of the 5-HT(3)A receptor. Thus these compounds have comparable, although less potent, behaviour than at some other Cys-loop receptors, demonstrating their actions are conserved across the family.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Gavande, Navnath
%A Karim, Nasiara
%A Johnston, Graham A R
%A Hanrahan, Jane R
%A Chebib, Mary
%T Identification of Benzopyran-4-one Derivatives (Isoflavones) as Positive Modulators of GABA(A) Receptors.
%B ChemMedChem
%D 2011
%C Germany
%I Wiley - V C H Verlag GmbH & Co. KGaA
%V 6
%N 8
%P 1340-6, 1317
%@ 1860-7187
%X 
%Z FOR Codes: 30401 30402


%0 Journal Article
%~ PubMed
%A Ng, Clarissa Kl
%A Kim, Hye-Lim
%A Gavande, Navnath
%A Yamamoto, Izumi
%A Kumar, Rohan J
%A Mewett, Kenneth N
%A Johnston, Graham Ar
%A Hanrahan, Jane R
%A Chebib, Mary
%T Medicinal chemistry of ρ GABAC receptors.
%B Future Medicinal Chemistry
%D 2011
%C United Kingdom
%I Future Science Ltd.
%V 3
%N 2
%P 197-209
%@ 1756-8927
%X The inhibitory neurotransmitter, GABA, is a low-molecular-weight molecule that can achieve many low-energy conformations, which are recognized by GABA receptors and transporters. In this article, we assess the structure-activity relationship profiles of GABA analogs at the ionotropic ?? GABA(C) receptor. Such studies have significantly contributed to the design and development of potent and selective agonists and antagonists for this subclass of GABA receptors. With these tools in hand, the role of ?? GABA(C) receptors is slowly being realized. Of particular interest is the development of selective phosphinic acid analogs of GABA and their potential use in sleep disorders, inhibiting the development of myopia, and in improving learning and memory.
%Z FOR Codes: 30401 111501


%0 Journal Article
%~ PubMed
%A Yow, Tin T
%A Pera, Elena
%A Absalom, Nathan
%A Heblinski, Marika
%A Johnston, Graham A R
%A Hanrahan, Jane R
%A Chebib, Mary
%T Naringin directly activates inwardly rectifying potassium channels at an overlapping binding site to tertiapin-Q.
%B British journal of pharmacology
%D 2011
%C United Kingdom
%I John Wiley & Sons Ltd.
%V 163
%N 5
%P 1017-33
%@ 0007-1188
%X G protein-coupled inwardly rectifying potassium (K(IR) 3) 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.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Gavande, Navnath
%A Johnston, Graham A R
%A Hanrahan, Jane R
%A Chebib, Mary
%T Microwave-enhanced synthesis of 2,3,6-trisubstituted pyridazines: application to four-step synthesis of gabazine (SR-95531).
%B Organic & biomolecular chemistry
%D 2010
%C United Kingdom
%I Royal Society of Chemistry
%V 8
%N 18
%P 4131-6
%@ 1477-0539
%X Microwave-enhanced, highly efficient protocols for the synthesis of synthetically and biologically important 2,3,6-trisubstituted pyridazine architectures have been developed by sequential amination/Suzuki coupling/alkylation reactions. This powerful strategy is an economical and highly chemoselective protocol for the synthesis of diversified pyridazines. The total synthesis of gabazine (SR-95531) has been achieved using a versatile strategy in four steps and 73% overall yield.
%Z FOR Codes: 30401


%0 Journal Article
%~ PubMed
%A Johnston, Graham A R
%A Chebib, Mary
%A Hanrahan, Jane R
%A Mewett, Kenneth N
%T Neurochemicals for the Investigation of GABA(C) Receptors.
%B Neurochemical research
%D 2010
%C United States
%I Springer New York LLC
%V 35
%N 12
%P 1970-7
%@ 1573-6903
%X GABA(C) receptors are being investigated for their role in many aspects of nervous system function including memory, myopia, pain and sleep. There is evidence for functional GABA(C) receptors in many tissues such as retina, hippocampus, spinal cord, superior colliculus, pituitary and the gut. This review describes a variety of neurochemicals that have been shown to be useful in distinguishing GABA(C) receptors from other receptors for the major inhibitory neurotransmitter GABA. Some selective agonists (including (+)-CAMP and 5-methyl-IAA), competitive antagonists (such as TPMPA, (??)-cis-3-ACPBPA and aza-THIP), positive (allopregnanolone) and negative modulators (epipregnanolone, loreclezole) are described. Neurochemicals that may assist in distinguishing between homomeric ??1 and ??2 GABA(C) receptors (2-methyl-TACA and cyclothiazide) are also covered. Given their less widespread distribution, lower abundance and relative structural simplicity compared to GABA(A) and GABA(B) receptors, GABA(C) receptors are attractive drug targets.
%Z FOR Codes: 30401 111501


%0 Journal Article
%~ PubMed
%A Skilbeck, Kj
%A Johnston, Gar
%A Hinton, T
%T Stress and GABA(A) Receptors.
%B Journal of neurochemistry
%D 2010
%C United Kingdom, United States
%I Wiley-Blackwell Publishing Ltd.
%V 112
%N 5
%P 1115-30
%@ 0022-3042
%X GABA(A) receptors are sensitive to subtle changes in the environment in both early-life and adulthood. These neurochemical responses to stress in adulthood are sex-dependent. Acute stress induces rapid changes in GABA(A) receptors in experimental animals, with the direction of the changes varying according to the sex of the animals and the stress-paradigm studied. These rapid alterations are of particular interest as they provide an example of fast neurotransmitter system plasticity that may be mediated by stress-induced increases in neurosteroids, perhaps via effects on phosphorylation and/or receptor trafficking. Interestingly, some studies have also provided evidence for long-lasting changes in GABA(A) receptors as a result of exposure to stressors in early-life. The short- and long-term stress sensitivity of the GABAergic system implicates GABA(A) receptors in the non-genetic etiology of psychiatric illnesses such as depression and schizophrenia in which stress may be an important factor.
%Z FOR Codes: 1115 1109


%0 Journal Article
%~ PubMed
%A Locock, Katherine
%A Johnston, Graham
%A Allan, Robin
%T GABA Analogues Derived from 4-Aminocyclopent-1-enecarboxylic Acid.
%B Neurochemical research
%D 2009
%C United States
%I Springer New York LLC
%V 34
%N 0
%P 1698-703
%@ 1573-6903
%X The incorporation of extra binding groups onto known ligands is a powerful tool for the development of more potent and selective agents at target sites such as the GABA receptors. In the present work we have attempted to build on the activity of the know potent GABA(A) agonist 4-ACP-3-CA and its cis and trans saturated analogues CACP and TACP. We have investigated reactions to add thiol substituents to the alpha,beta-unsaturated system of 4-ACP-3-CA. The reaction was successful with a limited number of thiols but gave products of mixed stereochemistry. The resultant thioether amino acids were screened for activity at human recombinant alpha(1)beta(2) gamma(2L) GABA(A) receptors. The most interesting derivative was the benzylthioether which acted as an antagonist with an IC(50) of 42 microM for the inhibition of a GABA EC(50) dose (50 microM). This study has shown that GABA analogues derived by thiol addition to 4-aminocyclopent-1-enecarboxylic acid display interesting antagonist activity at the alpha(1)beta(2)gamma(2L) GABA(A) receptor.
%Z FOR Codes: 111501 30401 111504 30401 111501 111504


%0 Journal Article
%~ PubMed
%A Chebib, Mary
%A Gavande, Navnath
%A Wong, Kit
%A Park, Anna
%A Premoli, Isabella
%A Mewett, Kenneth
%A Allan, Robin
%A Duke, Rujee
%A Johnston, Graham
%A Hanrahan, Jane
%T Guanidino Acids Act as rho1 GABA(C) Receptor Antagonists.
%B Neurochemical research
%D 2009
%C United States
%I Springer New York LLC
%V 34
%N 10
%P 1704-11
%@ 1573-6903
%X GABA(C) receptors play a role in myopia, memory-related disorders and circadian rhythms signifying a need to develop potent and selective agents for this class of receptors. Guanidino analogs related to glycine, beta-alanine and taurine were evaluated at human rho(1)GABA(C) receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. Of the 12 analogs tested, 8 analogs were active as antagonists and the remaining were inactive. (S)-2-guanidinopropionic acid (IC(50) = 2.2 microM) and guanidinoacetic acid (IC(50) = 5.4 microM; K (B) = 7.75 microM [pK (B) = 5.11 +/- 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the beta-alanine and GABA guanidino analogs showed reduced activity, indicating the distance between the carboxyl carbon and terminal nitrogen of the guanidino group is critical for activity. Substituting the C2-position of guanidinoacetic acid with various alkyl groups reduced activity indicating that steric effects may impact on activity. The results of this study contribute to the structure-activity-relationship profile required in developing novel therapeutic agents.
%Z FOR Codes: 30401 111501


%0 Journal Article
%~ PubMed
%A Chebib, Mary
%A Hinton, Tina
%A Schmid, Katrina L
%A Brinkworth, Darren
%A Qian, Haohua
%A Matos, Susana
%A Kim, Hye-Lim
%A Abdel-Halim, Heba
%A Kumar, Rohan J
%A Johnston, Graham A R
%A Hanrahan, Jane R
%T Novel, potent and selective GABAC antagonists inhibit myopia development and facilitate learning and memory.
%B The Journal of pharmacology and experimental therapeutics
%D 2009
%C United States
%I American Society for Pharmacology and Experimental
%V 328
%N 0
%P 448-57
%@ 1521-0103
%X 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 GABA(B/C) receptor antagonist (3-aminopropyl)-n-butylphosphinic acid (CGP36742 or SGS742). cis-[IC(50)(rho1) = 5.06 microM and IC(50)(rho2) = 11.08 microM; n = 4] and trans-3-ACPMPA [IC(50)(rho1) = 72.58 microM and IC(50)(rho2) = 189.7 microM; n = 4] seem competitive at GABA(C) receptors expressed in Xenopus laevis oocytes, having no effect as agonists (1 mM) but exerting weak antagonist (1 mM) effects on human GABA(A) and GABA(B) receptors. cis-3-ACPBPA was more potent and selective than the trans-compound, being more than 100 times more potent at GABA(C) than GABA(A) or GABA(B) receptors. cis-3-ACPBPA was further evaluated on dissociated rat retinal bipolar cells and dose-dependently inhibited the native GABA(C) receptor (IC(50) = 47 +/- 4.5 microM; 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 GABA(C) 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 GABA(C) activity.
%Z FOR Codes: 111501 110903


%0 Journal Article
%~ PubMed
%A Mewett, Kenneth N
%A Fernandez, Sebastian P
%A Pasricha, Anmol K
%A Pong, Alice
%A Devenish, Steven O
%A Hibbs, David E
%A Chebib, Mary
%A Johnston, Graham A R
%A Hanrahan, Jane R
%T Synthesis and biological evaluation of flavan-3-ol derivatives as positive modulators of GABAA receptors.
%B Bioorganic & Medicinal Chemistry
%D 2009
%C United Kingdom
%I Pergamon
%V 17
%N 20
%P 7156-7173
%@ 0968-0896
%X We herein describe the synthesis and positive modulatory activities of a small library of flavan-3-ol derivatives on alpha(1)beta(2)gamma(2L) GABA(A) receptors. Structure-activity relationships of various substituents on the A, B and C rings were evaluated in a functional electrophysiological assay. A trans configuration and a 3-acetoxy moiety are essential for activity. Substitution of the B ring appears to be well tolerated, with substituents on the A ring playing a major role in determining activity.
%Z FOR Codes: 111501


%0 Book Section
%A Hanrahan, Jane R
%A Johnston, Graham
%T Synthesis of gamma-aminobutyric acid analogs
%B Amino Acids, Peptides and Proteins in Organic Chemistry. Volume 1 - Origins and Synthesis of Amino Acids
%D 2009
%C Germany
%I Wiley-VCH
%V 
%N 
%P 573-689
%@ 9783527320967
%E Hughes, Andrew B
%X 
%Z FOR Codes: 30406


%0 Journal Article
%~ PubMed
%A Fernandez, Sebastian
%A Nguyen, Michael
%A Yow, Tin
%A Chu, Cindy
%A Johnston, Graham
%A Hanrahan, Jane
%A Chebib, Mary
%T The Flavonoid Glycosides, Myricitrin, Gossypin and Naringin Exert Anxiolytic Action in Mice.
%B Neurochemical research
%D 2009
%C United States
%I Springer New York LLC
%V 34
%N 10
%P 1867-75
%@ 1573-6903
%X The consumption of flavonoid-rich foods, in particular fruits and vegetables, has been epidemiologically associated with a reduced risk of heart disease, neurodegenerative disease, cancer and other chronic diseases. Flavonoid glycosides, the main class of flavonoids, have been shown to exert CNS-mediated activities, particularly as sedative-hypnotics, analgesics or both, nevertheless no studies have evaluated these agents in anxiety. This study assessed the potential anxiolytic effect of three flavonoid glycosides, myrcitrin, naringin and gossypin, in the elevated plus maze test (EPM). Myricitrin (1 mg/kg) was effective on the EPM showing a clear anxiolytic effect with no signs of sedation. However, higher doses showed possible sedative and myorelaxation effects. Gossypin and naringin both shared a similar profile, with low doses (1 mg/kg) inducing a robust anxiolytic effect which diminished with increasing doses of the flavonoids. Higher doses of these two flavonoids showed a dramatic increase in the open arm exploration accompanied by a decrease in locomotor activity. Hence, naringin (30 mg/kg) and gossypin (30 mg/kg) induce both anxiolytic and sedative effects. These results suggest that flavonoid glycosides have the potential to exert a range of CNS-mediated biological activities.
%Z FOR Codes: 30401 111501


%0 Journal Article
%~ PubMed
%A Abdel-Halim, Heba
%A Hanrahan, Jane R
%A Hibbs, David E
%A Johnston, Graham A R
%A Chebib, Mary
%T A molecular basis for agonist and antagonist actions at GABA(C) receptors.
%B Chemical Biology & Drug Design
%D 2008
%C Denmark
%I Wiley-Blackwell Munksgaard
%V 71
%N 4
%P 306-327
%@ 1747-0285
%X We modelled the N-terminal ligand-binding domain of the rho1 GABA(C) 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 rho1 GABA(C) 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 A(3). A detailed analysis of the interaction between the rho1 GABA(C) receptor model and the docked ligands revealed possible H-bonds and cation-pi 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.
%Z FOR Codes: 110502 110902


%0 Journal Article
%~ PubMed
%A Fernandez, Sebastian P
%A Mewett, Kenneth N
%A Hanrahan, Jane R
%A Chebib, Mary
%A Johnston, Graham A R
%T Flavan-3-ol derivatives are positive modulators of GABA(A) receptors with higher efficacy for the alpha(2) subtype and anxiolytic action in mice.
%B Neuropharmacology
%D 2008
%C United Kingdom
%I Pergamon
%V 55
%N 5
%P 900-7
%@ 0028-3908
%X Recent genetic and pharmacological studies have demonstrated that alpha(2)-containing GABA(A) receptors mediate the anxiolytic effects of benzodiazepines, setting a new strategy in developing novel, non-sedative anxiolytic agents. In this study we show that stereoisomers of 3-acetoxy-4''-methoxyflavan are positive modulators of recombinant alpha(1,2,3,5)beta(2)gamma(2L) and alpha(1)beta(2) GABA(A) receptors expressed in Xenopus laevis oocytes. GABA(C) receptors are insensitive to modulation by these compounds. In each case, the enhancement was evident at low micromolar concentrations and occurred independently of the classical high affinity benzodiazepine site, as it could not be blocked by the antagonist flumazenil. Importantly, the compound Fa131 was significantly more efficacious at enhancing GABA-induced currents (EC(5)) at alpha(2)beta(2)gamma(2L) receptors compared to alpha(1)beta(2)gamma(2L), alpha(3)beta(2)gamma(2L) and alpha(5)beta(2)gamma(2L) receptors (E(max)=21.0+/-1.7 times, compared to 8.5+/-0.7 times at alpha(1)-, 9.5+/-0.6 times at alpha(3)- and 5.2+/-0.4 times at alpha(5)-contaning GABA(A) receptors), suggesting a potential use as an anxiolytic. In mice, this agent (1-30mg/kg i.p.) induced anxiolytic-like action in two unconditioned models of anxiety: the elevated plus maze and the light/dark paradigms. No sedative or myorelaxant effects were detected using the hole board, actimeter and horizontal wire tests, and only weak barbiturate-potentiating effects on the loss of righting reflex test. Fa131 demonstrated improved segregation of anxiolytic and sedative doses when compared to the non-selective agonist diazepam. Finally, flavan derivatives highlight the potential of targeting non-benzodiazepine allosteric sites in the search for new anxioselective drugs.
%Z FOR Codes: 110903 110502


%0 Journal Article
%~ PubMed
%A Kumar, Rohan
%A Chebib, Mary
%A Hibbs, David
%A Kim, Hye-Lim
%A Johnston, Graham
%A Salam, Noeris
%A Hanrahan, Jane
%T Novel gamma-Aminobutyric Acid rho1 Receptor Antagonists; Synthesis, Pharmacological Activity and Structure-Activity Relationships.
%B Journal of medicinal chemistry
%D 2008
%C United States
%I American Chemical Society
%V 51
%N 13
%P 3825-40
%@ 0022-2623
%X 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.
%Z FOR Codes: 110502 110903


%0 Journal Article
%~ PubMed
%A Skilbeck, K J
%A Hinton, T
%A Johnston, G A R
%T Sex-differences and stress: effects on regional high and low affinity [3H]GABA binding.
%B Neurochemistry International
%D 2008
%C United Kingdom
%I Elsevier
%V 52
%N 6
%P 1212-1219
%@ 0197-0186
%X Sex-differences are observed in the GABAergic neurotransmitter system both at rest and following acute stress, yet the brain regions and functional implications of these differences are unknown. We examined sex-differences in the number of low- and high-affinity [3H]GABA binding sites in various brain regions of male and female mice and the effect of stress on such sex-differences. Male (n=6) and female (n=6) QS mice were exposed to a brief swim stress (3 min at 32+/-1 degrees C) either individually or with cage-mates whilst control males (n=6) and females (n=6) remained undisturbed in the home cage. Using quantitative receptor autoradiography, sections of mouse brain were labelled with either 30 or 1000 nM [3H]GABA to label high or low affinity binding sites, respectively. Results indicated that males had more low affinity [3H]GABA binding sites in various forebrain cortical regions but less high affinity binding sites in many of these regions compared with females. Forced swim stress-induced rapid changes in forebrain GABA binding sites in females and group stressed males, suggesting a mechanism for rapid GABAergic adaptations. However the number of functional binding sites for GABA in certain forebrain regions was altered by stress in opposite directions in males and females, such that baseline sex-differences were removed following stress. These results exemplify sex-differences in brain chemical function and stress responses, and are of potential importance for understanding sex-differences in response to GABAergic compounds and disorders with sex and stress as predisposing factors.
%Z FOR Codes: 110903


%0 Journal Article
%~ PubMed
%A Chebib, Mary
%A Hanrahan, Jane R
%A Kumar, Rohan J
%A Mewett, Kenneth N
%A Morriss, Gwendolyn
%A Wooller, Soraya
%A Johnston, Graham A R
%T (3-Aminocyclopentyl)methylphosphinic acids: Novel GABA(C) receptor antagonists.
%B Neuropharmacology
%D 2007
%C UK
%I Pergamon
%V 52
%N 3
%P 779-87
%@ 0028-3908
%X Our understanding of the role GABA(C) receptors play in the central nervous system is limited due to a lack of specific ligands. Here we describe the pharmacological effects of (+/-)-cis-3- and (+/-)-trans-3-(aminocyclopentyl)methylphosphinic acids ((+/-)-cis- and (+/-)-trans-3-ACPMPA) as novel ligands for the GABA(C) receptor showing little activity at GABA(A) or GABA(B) receptors. (+/-)-cis-3-ACPMPA has similar potency to (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at human recombinant rho1 (K(B)=1.0+/-0.2microM) and rat rho3 (K(B)=5.4+/-0.8microM) but is 15 times more potent than TPMPA on human recombinant rho2 (K(B)=1.0+/-0.3microM) GABA(C) receptors expressed in Xenopus oocytes. (+/-)-cis- and (+/-)-trans-3-ACPMPA are novel lead compounds for developing into more potent and selective GABA(C) receptor antagonists with increased lipophilicity for in vivo studies.
%Z FOR Codes: 110502


%0 Journal Article
%~ PubMed
%A Skilbeck, Kelly J
%A O'Reilly, Jennifer N
%A Johnston, Graham A R
%A Hinton, Tina
%T Antipsychotic drug administration differentially affects [(3)H]muscimol and [(3)H]flunitrazepam GABA(A) receptor binding sites.
%B Progress in neuro-psychopharmacology & biological psychiatry
%D 2007
%C US, Canada.
%I Elsevier Inc.
%V 32
%N 0
%P 492-8
%@ 0278-5846
%X Post-mortem studies of the human brain indicate that certain GABA(A) receptor subtypes may be differentially altered in schizophrenia. Increased binding to the total population of GABA(A) receptors using [3H]muscimol is observed in the post-mortem schizophrenic brain, yet a proportion of these receptors which bind benzodiazepines and are labelled with [3H]flunitrazepam, show decreased or unaltered expression. Data from animal studies suggest that antipsychotic drugs alter GABA(A) receptor expression in a subtype selective manner, but in the opposite direction to that observed in schizophrenia. To broaden our understanding of the effects of antipsychotic drugs on GABA(A) receptors, we examined the saturation binding maximum (B(max)) and binding affinity (K(D)) of [3H]muscimol and [3H]flunitrazepam in the prefrontal cortex (PFC), hippocampus and thalamus of male SD rats that received a sucrose solution containing either haloperidol (1.5 mg/kg), olanzapine (6.5 mg/kg) or no drug daily for up to 28 days using quantitative receptor autoradiography. [3H]Muscimol binding density was increased most prominently in the PFC after 7 days, with larger and more prolonged effects being induced by the atypical antipsychotic drug olanzapine in subcortical regions. While no changes were observed in [3H]muscimol binding in any region after 28 days of drug administration, [3H]flunitrazepam binding density (B(max)) was increased for both antipsychotic treatments in the PFC only. These findings confirm that the subset of GABA(A) receptors sensitive to benzodiazepines are regulated differently from other GABA(A) receptor subtypes following antipsychotic drug administration, in a time- and region-dependent manner.
%Z FOR Codes: 110502


%0 Journal Article
%~ PubMed
%A Hinton, Tina
%A Chebib, Mary
%A Johnston, Graham A R
%T Enantioselective actions of 4-amino-3-hydroxybutanoic acid and (3-amino-2-hydroxypropyl)methylphosphinic acid at recombinant GABA(C) receptors.
%B Bioorganic & medicinal chemistry letters
%D 2007
%C UK
%I Pergamon
%V 18
%N 1
%P 402-4
%@ 0960-894X
%X The R- and S-enantiomers of 4-amino-3-hydroxybutanoic acid (GABOB) were full agonists at human recombinant rho1 GABA(C) receptors. Their enantioselectivity (R>S) matched that reported for their agonist actions at GABA(B) receptors, but was the opposite to that reported at GABA(A) receptors (S>R). The corresponding methylphosphinic acid analogues proved to be rho1 GABA(C) receptor antagonists with R(+)-CGP44533 being more potent than S(-)-CGP44532, thus showing the opposite enantioselectivity to the agonists R(-)- and S(+)-GABOB. These studies highlight the different stereochemical requirements for the hydroxy group in these analogues at GABA(A), GABA(B) and GABA(C) receptors.
%Z FOR Codes: 110502


%0 Journal Article
%~ PubMed
%A Carland, Jane E
%A Johnston, Graham A R
%A Chebib, Mary
%T Relative impact of residues at the intracellular and extracellular ends of the human GABA(C) rho1 receptor M2 domain on picrotoxinin activity.
%B European journal of pharmacology
%D 2007
%C Po Box 211, Amsterda
%I Elsevier Science Bv
%V 580
%N 1-2
%P 27-35
%@ 0014-2999
%X The relative impact on picrotoxinin activity of residues at the intracellular (2'' and 6'' residues) and extracellular (15'' and 17'' residues) ends of the second transmembrane (M2) domain of the human gamma-aminobutyric acid-C (GABA(C)) rho1 receptor was investigated. A series of GABA(C) rho1 subunits were produced containing either single or multiple mutations at the positions of interest. Wild-type and mutant subunits (containing one or more of the following mutations: P2''S, T6''M, I15''N, G17''H) were expressed in Xenopus oocytes and characterized using agonists, partial agonists and antagonists. Changes in agonist activity were observed for mutant receptors. Most notably, mutation at the 2'' position resulted in decreased agonist potency, while mutation at the 15'' and 17'' residues increased agonist potency. The affinity of the competitive antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA) was unchanged compared to wild-type at all mutant receptors. Of the four residues studied, mutation of residues at the 2'' and 6'' positions had the greatest impact on picrotoxinin activity. Inclusion of the P2''S mutation typically produced receptors with increased picrotoxinin potency, while the T6''M mutation reduced picrotoxinin potency. Picrotoxinin is a mixed antagonist at wild-type and all mutant receptors, with the exception of the double mutant rho1P2''S/T6''M receptors at which the non-competitive component was isolated. It is proposed that the contribution of M2 domain residues to picrotoxinin activity is potentially two-fold: (1) their role as a potential picrotoxinin binding site within the pore; and (2) they are critical for receptor activation properties of the receptor, thus may alter the allosteric mechanism of picrotoxinin.
%Z FOR Codes: 110502 110903


%0 Journal Article
%~ PubMed
%A Skilbeck, Kelly J
%A O'Reilly, Jennifer N
%A Johnston, Graham A R
%A Hinton, Tina
%T The effects of antipsychotic drugs on GABAA receptor binding depend on period of drug treatment and binding site examined.
%B Schizophrenia research
%D 2007
%C Netherlands
%I Elsevier BV
%V 90
%N 1-3
%P 76-80
%@ 0920-9964
%X Changes in GABA(A) receptors are observed in schizophrenia, with benzodiazepine-sensitive GABA(A) receptor subtypes being affected differently to other subtypes. However, long-term antipsychotic drug use in schizophrenia may underlie these changes. To test this, we examined the effects of administering a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug on the GABA(A) receptor agonist (orthosteric) and benzodiazepine (allosteric) binding sites in rat prefrontal cortex. As antipsychotic drugs have delayed maximal therapeutic effects we also examined different drug treatment periods. Male SD rats received a sucrose solution containing either haloperidol (1.5 mg/kg), olanzapine (6.5 mg/kg) or no drug daily for either 7, 14 or 28 days. Sections of rat brain were then labelled with [(3)H]muscimol, which labels the total population of GABA(A) receptors, or the benzodiazepine site ligand [(3)H]flunitrazepam in separate saturation binding experiments using quantitative receptor autoradiography. [(3)H]Muscimol binding was enhanced in the prefrontal cortex after 7 days but no differences were observed after longer periods of drug administration. In contrast there was a delayed increase in density of benzodiazepine-sensitive GABA(A) receptors in the PFC, suggesting that antipsychotic drugs have different effects on different GABA(A) receptor subtypes. These changes in the properties of GABA(A) receptor binding following antipsychotic drug administration are not consistent with those observed in schizophrenia and suggest a ''reshuffling'' in GABA(A) receptor subtypes over time.
%Z FOR Codes: 110502


%0 Journal Article
%~ Isi
%A Skilbeck, K. J.
%A O'Reilly, J. N.
%A Johnston, G. A. R.
%A Hinton, T.
%T Antipsychotic drug effects on GABA(A) receptors.
%B Australian and New Zealand Journal of Psychiatry
%D 2006
%C UK
%I Taylor & Francis Ltd
%V 40
%N 
%P A125-A125
%@ 
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Fernández, Sebastián P
%A Wasowski, Cristina
%A Loscalzo, Leonardo M
%A Granger, Renee E
%A Johnston, Graham A R
%A Paladini, Alejandro C
%A Marder, Mariel
%T Central nervous system depressant action of flavonoid glycosides.
%B European journal of pharmacology
%D 2006
%C Netherlands
%I Elsevier BV
%V 539
%N 3
%P 168-76
%@ 0014-2999
%X The pharmacological effects on the central nervous system (CNS) of a range of available flavonoid glycosides were explored and compared to those of the glycosides 2S-hesperidin and linarin, recently isolated from valeriana. The glycosides 2S-neohesperidin, 2S-naringin, diosmin, gossipyn and rutin exerted a depressant action on the CNS of mice following i.p. injection, similar to that found with 2S-hesperidin and linarin. We demonstrate in this work that these behavioural actions, as measured in the hole board, thiopental induced sleeping time and locomotor activity tests, are unlikely to involve a direct action on gamma-aminobutyric acid type A (GABA(A)) receptors. The corresponding aglycones were inactive, pointing to the importance of the sugar moieties in the glycosides in their CNS depressant action following systemic administration. The pharmacological properties of the flavonoid glycosides studied here, in addition to our previous results with hesperidin and linarin, opens a promising new avenue of research in the field.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Hanrahan, Jane R
%A Mewett, Kenneth N
%A Chebib, Mary
%A Matos, Susana
%A Eliopoulos, Con T
%A Crean, Colm
%A Kumar, Rohan J
%A Burden, Peter
%A Johnston, Graham A R
%T Diastereoselective synthesis of (+/-)-(3-aminocyclopentane)alkylphosphinic acids, conformationally restricted analogues of GABA.
%B Organic & biomolecular chemistry
%D 2006
%C United Kingdom
%I Royal Society of Chemistry
%V 4
%N 13
%P 2642-2649
%@ 1477-0520
%X A divergent synthesis of both diastereoisomers of (+/-)-(3-aminocyclopentane)alkylphosphinic acid is described. Both diastereoisomers are obtained in 5 steps from the key (+/-)-(3-hydroxycyclopent-1-ene)alkylphosphinate esters which are prepared via a palladium catalysed C-P bond forming reaction.
%Z FOR Codes: 111503


%0 Journal Article
%~ PubMed
%A Crittenden, Deborah L
%A Park, Anna
%A Qiu, Jian
%A Silverman, Richard B
%A Duke, Rujee K
%A Johnston, Graham A R
%A Jordan, Meredith J T
%A Chebib, Mary
%T Enantiomers of cis-constrained and flexible 2-substituted GABA analogues exert opposite effects at recombinant GABA(C) receptors.
%B Bioorganic & medicinal chemistry
%D 2006
%C United Kingdom
%I Pergamon
%V 14
%N 2
%P 447-55
%@ 0968-0896
%X The effects of the enantiomers of a number of flexible and cis-constrained GABA analogues were tested on GABA(C) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (1S,2R)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((+)-CAMP), a potent and full agonist at the rho1 (EC(50) approximately 40 microM, I(max) approximately 100%) and rho 2 (EC(50) approximately 17 microM, I(max) approximately 100%) receptor subtypes, was found to be a potent partial agonist at rho3 (EC(50) approximately 28 microM, I(max) approximately 70%). (1R,2S)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((-)-CAMP), a weak antagonist at human rho1 (IC(50) approximately 890 microM) and rho2 (IC(50) approximately 400 microM) receptor subtypes, was also found to be a moderately potent antagonist at rat rho3 (IC(50) approximately 180 microM). Similarly, (1R,4S)-4-aminocyclopent-2-ene-1-carboxylic acid ((+)-ACPECA) was a full agonist at rho1 (EC(50) approximately 135 microM, I(max) approximately 100%) and rho2 (EC(50) approximately 60 microM, I(max) approximately 100%), but only a partial agonist at rho3 (EC(50) approximately 112 microM, I(max) approximately 37%), while (1S,4R)-4-aminocyclopent-2-ene-1-carboxylic acid ((-)-ACPECA) was a weak antagonist at all three receptor subtypes (IC(50)>>300 microM). 4-Amino-(S)-2-methylbutanoic acid ((S)-2MeGABA) and 4-amino-(R)-2-methylbutanoic acid ((R)-2MeGABA) followed the same trend, with (S)-2MeGABA acting as a full agonist at the rho1 (EC(50) approximately 65 microM, I(max) approximately 100%), and rho2 (EC(50) approximately 20 microM, I(max) approximately 100%) receptor subtypes, and a partial agonist at rho3 (EC(50) approximately 25 microM, I(max) approximately 90%). (R)-2MeGABA, however, was a moderately potent antagonist at all three receptor subtypes (IC(50) approximately 16 microM at rho1, 125 microM at rho2 and 35 microM at rho3). On the basis of these expanded biological activity data and the solution-phase molecular structures obtained at the MP2/6-31+G* level of ab initio theory, a rationale is proposed for the genesis of this stereoselectivity effect.
%Z FOR Codes: 110502


%0 Journal Article
%~ PubMed
%A Huang, S H
%A Duke, R K
%A Chebib, M
%A Sasaki, K
%A Wada, K
%A Johnston, G A R
%T Mixed antagonistic effects of bilobalide at rho1 GABAC receptor.
%B Neuroscience
%D 2006
%C 9650 Rockville Pike,
%I Pergamon-Elsevier Science Ltd
%V 137
%N 2
%P 607-17
%@ 0306-4522
%X Bilobalide was found to be a moderately potent antagonist with a weak use-dependent effect at recombinant human rho(1) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp methodology. Antagonism of bilobalide at homomeric rho(1) GABA(C) receptors appeared to be mixed. At low concentration, bilobalide (3 microM) caused a parallel right shift and surmountable GABA maximal response of the GABA dose-response curve characteristic of a competitive antagonist. At high concentrations, bilobalide (10-100 microM) caused nonparallel right shifts and reduced maximal GABA responses of GABA dose-response curves characteristic of a noncompetitive antagonist. The potency of bilobalide appears to be dependent on the concentrations of GABA and was more potent at lower GABA concentrations. The mechanism of action of bilobalide at rho(1) GABA(C) receptors appears to be similar to that of the chloride channel blocker picrotoxinin.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Johnston, Graham A R
%A Hanrahan, Jane R
%A Chebib, Mary
%A Duke, Rujee K
%A Mewett, Kenneth N
%T Modulation of ionotropic GABA receptors by natural products of plant origin.
%B Advances in pharmacology (San Diego, Calif.)
%D 2006
%C United States
%I Academic Press
%V 54
%N 
%P 285-316
%@ 1054-3589
%X 
%Z FOR Codes: 110502 110903