Pharmacological differentiation of kainate receptors on neonatal rat spinal motoneurones and dorsal roots

Thomas, Nicola; Hawkins, Lynda M.; Miller, Jacqueline C.; Troop, Helen M; Roberts, Peter; Jane, David E.

doi:10.1016/s0028-3908(98)00124-5

Cited by 21 publications

(26 citation statements)

References 24 publications

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“…The natural product willardiine acts as an agonist at AMPA receptors and a range of willardiine analogues have been synthesised with selectivity for either AMPA or GluR5‐containing kainate receptors depending on the nature of the 5‐substituent on the uracil ring (Evans et al ., 1980; Patneau et al ., 1992; Wong et al ., 1994; Jane et al ., 1997). For example, ( S )‐5‐iodowillardiine is a highly selective GluR5 agonist whereas ( S )‐5‐fluorowillardiine is an AMPA receptor agonist, which binds with higher affinity to GluR1 or GluR2 compared to GluR3 or GluR4 (Jane et al ., 1997; Thomas et al ., 1998; Varney et al ., 1998).…”

Section: Introductionmentioning

confidence: 99%

Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists

Troop

Dolman

et al. 2003

British J Pharmacology

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1 The natural product willardiine is an AMPA receptor agonist. We have examined the structural changes required to convert willardiine into an antagonist at AMPA and kainate receptors. Structureactivity analysis has been carried out to discover the structural features required to increase the potency and/or selectivity of the antagonists at AMPA or kainate receptors. 2 Reduction of the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) has been used to investigate AMPA receptor antagonist activity. To examine antagonist activity at kainate receptors, the ability of compounds to depress kainate-induced depolarisations of dorsal root fibres was assessed. 3 Blocking ionisation of the uracil ring by adding a methyl group to the N 3 position was not sufficient to convert willardiine into an antagonist. However, willardiine derivatives with a side-chain bearing a carboxylic acid group at the N 3 -position of the uracil ring could antagonise AMPA and kainate receptors. 4 S stereochemistry was optimal for antagonism. When compounds with differing interacidic group chain lengths were compared, a group chain length of two methylene groups was preferable for AMPA receptor antagonism in the series of compounds bearing a carboxyalkyl side chain (UBP275, UBP277 and UBP279 reduced the fDR-VRP with IC 50 values of 287741, 23.873.9 and 136717 mm, respectively). For kainate receptor antagonism, two or three methylene groups were almost equally acceptable (UBP277 and UBP279 reduced dorsal root kainate responses with apparent K D values of 73.174.5 and 60.574.1 mm, respectively). 5 Adding an iodo group to the 5-position of UBP277 and UBP282 enhanced activity at kainate receptors (UBP291 and UBP301 antagonised kainate responses on the dorsal root with apparent K D values of 9.8371.62 and 5.9470.63 mm, respectively). 6 The most useful antagonist identified in this study was UBP301, which was a potent and B30-fold selective kainate receptor antagonist. UBP282 may also be of use in isolating a non-GluR5-mediated kainate response.

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Section: Introductionmentioning

confidence: 99%

Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists

Troop

Dolman

et al. 2003

British J Pharmacology

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“…Thus ATPA and 5-I-will have similarly high affinity and selectivity for iGluR5. However, ATPA is approximately 10-fold weaker than (S)-5-I-will at depolarizing immature dorsal roots (ECso values 1.3 ± 0.3 pmolll and 0.127 ± 0.01 pmolll respectively (THOMAS et al 1998)). In agreement with earlier work on DRG cells (WONG et ai.…”

Section: Amongst Recent Examples (2s4r)-4-methylglutamate «2s4r)-4mgmentioning

confidence: 89%

Glutamate Receptor Ion Channels: Activators and Inhibitors

Jane¹,

Tse²,

Skifter³

et al. 2000

Pharmacology of Ionic Channel Function: Activators and Inhibitors

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The classification of excitatory amino acid (EAA) receptors into N-methyl-oaspartic acid (NMDA) and non-NMDA receptors was based mainly on the discovery of selective agonists and antagonists (for a review see WATKINS and EVANS 1981). Thus the selective NMDA receptor antagonist, o-aaminoadipate blocked responses due to NMDA but not those due to quisqualate or kainate in the frog and rat spinal cord. Evidence for more than one type of non-NMDA receptor came from the observation that responses due to quisqualate but not those due to kainate are depressed by L-glutamic acid diethyl ester (GDEE) (McLENNAN and LOOGE 1979; while responses to kainate can be selectively antagonized by y"oglutamylglycine (rDGG) . In addition, receptors present on dorsal root fibers were shown to be sensitive to kainate but not quisqualate ). These observations resulted in the classification of EAA receptors into NMDA, quisqualate and kainate receptors. Such receptors are linked to ionic fluxes and are now known as ionotropic glutamate receptors (iGluRs) as distinct from the more recently discovered metabotropic glutamate receptors (mGluRs) linked to G-protein coupled metabolic changes (CONN and PIN 1997). The isoxazole analogue, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) was reported to be more selective for the quisqualate type of iGluR than quisqualate itself (KROGSGAARO-LARSEN et al. 1980 and this led to this ionotropic receptor being renamed the AMPA receptor to avoid confusion with quisqualate-activated mGluRs (MONAGHAN et al. 1989;). Molecular biology has identified a large number of subtypes of both iGluRs and mGluRs.Progress in defining the role of EAA receptors in CNS function has also followed the development of receptor-selective antagonists. With the availability of NMDA receptor antagonists, it was possible to demonstrate a role of NMDA receptors in polysynaptic responses in the vertebrate spinal cord EVANS et al. 1979) and in hippocampal long term potentiation (COLLINGRIDGE et al. 1983;HARRIS et al. 1984

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“…1) have been used as standard KA receptor agonists, in spite of their showing nondesensitizing responses at AMPA receptors. More selective KA receptor agonist activities have recently been described for (S)-ATPA, 45,76 (S)-thio-ATPA, 77 and (S)-5-Iwillardiine 31,78 (Fig. 12).…”

Section: Ka Receptor Agonists and Ka Analogsmentioning

confidence: 92%

Stereostructure–activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors

Johansen¹,

Greenwood²,

Frydenvang³

et al. 2003

Chirality

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(S)-Glutamic acid (Glu), the major excitatory neurotransmitter in the central nervous system, operates through ionotropic as well as metabotropic receptors and is considered to be involved in certain neurological disorders and degenerative brain diseases that are currently without any satisfactory therapeutic treatment. Until recently, development of selective Glu receptor agonists had mainly been based on lead compounds, which were frequently naturally occurring excitants structurally related to Glu. These Glu receptor agonists generally contain heterocyclic acidic moieties, which has stimulated the use of bioisosteric replacement approaches for the design of subtype-selective agonists. Furthermore, most of these leads are conformationally restricted and stereochemically well-defined Glu analogs. Crystallization of the agonist binding domain of the GluR2 subunit of the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of ionotropic Glu receptors in the presence or absence of an agonist has provided important information about ligand-receptor interaction mechanisms. The availability of these binding domain crystal structures has formed the basis for rational design of ligands, especially for the AMPA and kainate subtypes of ionotropic Glu receptors. This mini-review will focus on structure-activity relationships on AMPA and kainate receptor agonists with special emphasis on stereochemical and three-dimensional aspects.

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Pharmacological differentiation of kainate receptors on neonatal rat spinal motoneurones and dorsal roots

Cited by 21 publications

References 24 publications

Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists

Structural requirements for novel willardiine derivatives acting as AMPA and kainate receptor antagonists

Glutamate Receptor Ion Channels: Activators and Inhibitors

Stereostructure–activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors

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