The novel antagonist 3‐CBW discriminates between kainate receptors expressed on neonatal rat motoneurones and those on dorsal root C‐fibres

More, Julia C. A.; Troop, Helen M; Jane, David E.

doi:10.1038/sj.bjp.0704957

Cited by 15 publications

(44 citation statements)

References 37 publications

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“…To compare the antagonists for activity at AMPA receptors, their ability to depress the fast component of the dorsal root‐evoked ventral root potential (fDR‐VRP) in the neonatal rat hemisected spinal cord preparation was measured. As reported previously, the fDR‐VRP has been shown to be evoked by the stimulation of AMPA receptors and can therefore be used as a convenient method to compare AMPA receptor antagonists using native receptors (More et al ., 2002b).…”

Section: Introductionmentioning

confidence: 83%

“…A number of studies have demonstrated the conversion of glutamate receptor agonists into antagonists by extending the chain length between the α ‐carboxylic acid and the terminal acidic group (Davies et al ., 1982; Krogsgaard‐Larsen et al ., 1991; Madsen et al ., 1996; Jane et al ., 2000). We recently demonstrated that the agonist willardiine could be converted into an antagonist of AMPA and kainate receptors by increasing the interacidic group chain length when it was shown that 3‐CBW (( S )‐3‐(4‐carboxybenzyl)willardiine, UBP282) is an antagonist of AMPA receptors on motor neurones and kainate receptors on dorsal root C‐fibres (More et al ., 2002a, b).…”

Section: Introductionmentioning

confidence: 99%

“…To investigate the ability of the novel compounds to antagonise kainate receptors, their ability to depress kainate‐induced depolarisations of neonatal rat dorsal roots was assessed. Previous studies have shown that this preparation contains predominantly kainate receptors of the GluR5 subtype (Bettler et al ., 1990; Partin et al ., 1993), although possibly combined with KA1 or KA2 (Fletcher & Lodge, 1996), making it useful for the examination of selective kainate receptor antagonists using a native receptor population (Agrawal & Evans, 1986; Thomas et al ., 1998; More et al ., 2002a, b).…”

Section: Introductionmentioning

confidence: 99%

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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: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…The prototypic GluK1-selective antagonists, such as LY382884 (O'Neill et al, 1998) have low micromolar potency. We therefore developed a series of KAR antagonists based on the structure of the AMPA receptor agonist willardiine (More et al, 2002; More et al, 2003). Over the past few years, a combination of structure-activity relationship studies and homology models (More et al, 2004; Dolman et al, 2005; Dolman et al, 2006) have been used to create novel compounds that show a marked selectivity for GluK1 with potencies ranging from micromolar (UBP296, UBP302 and UBP304) to nanomolar (UBP310).…”

Section: Introductionmentioning

confidence: 99%

ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function

et al. 2009

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Kainate receptors (KARs) are involved in both NMDA receptor-independent long-term potentiation (LTP) and synaptic facilitation at mossy fibre synapses in the CA3 region of the hippocampus. However, the identity of the KAR subtypes involved remains controversial. Here we used a highly potent and selective GluK1 (formerly GluR5) antagonist (ACET) to elucidate roles of GluK1-containing KARs in these synaptic processes. We confirmed that ACET is an extremely potent GluK1 antagonist, with a K b value of 1.4 ± 0.2 nM. In contrast, ACET was ineffective at GluK2 (formerly GluR6) receptors at all concentrations tested (up to 100 μM) and had no effect at GluK3 (formerly GluR7) when tested at 1 μM. The X-ray crystal structure of ACET bound to the ligand binding core of GluK1 was similar to the UBP310-GluK1 complex. In the CA1 region of hippocampal slices, ACET was effective at blocking the depression of both fEPSPs and monosynaptically-evoked GABAergic transmission induced by ATPA, a GluK1 selective agonist. In the CA3 region of the hippocampus, ACET blocked the induction of NMDA receptor-independent mossy fibre LTP. To directly investigate the role of pre-synaptic GluK1-containing KARs we combined patch-clamp electrophysiology and 2-photon microscopy to image Ca 2+ dynamics in individual giant mossy fibre boutons. ACET consistently reduced short-term facilitation of pre-synaptic calcium transients induced by 5 action potentials evoked at 20-25 Hz. Taken together our data provide further evidence for a physiological role of GluK1-containing KARs in synaptic facilitation and LTP induction at mossy fibre-CA3 synapses.

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“…Drugs are being developed that specifically target glutamate receptor subunits. (RS)-α-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionic acid (ATPA) is a specific agonist of GluR5-containing kainate receptors [152]; (RS)-2-amino-3-(4-chloro-3-hydroxy-5-isoxazolyl) propionic acid (CI-HIBO) is the most subtype selective agonist reported to date on AMPA GluR1/2 subunits [153]; 4-(2-(phenylsulfonylamino)ethylthio)-2,6-difluorophenoxyacetamide (PEPA) is a highly specific floppreferring allosteric modulator of AMPA receptor desensitisation [154]; and (S)-3-(4-carboxybenzyl)willardiine (3-CBW) discriminates between kainate receptors expressed on neonatal rat motor neurons and those on dorsal root Cfibres [155]. The development of drugs that target specific receptor subunits could allow more subtle effects on function after spinal lesions.…”

Section: Ionotropic Receptorsmentioning

confidence: 99%

Pharmacological Approaches to Functional Recovery After Spinal Injury

Parker

2005

CDTCNSND

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Locomotion results from the activity in neural networks in the spinal cord that together with sensory and descending inputs generate coordinated motor outputs. Descending inputs include glutamatergic, monoaminergic, and peptidergic pathways. Spinal injuries interrupt these descending pathways, resulting in the disruption or loss of function. Drugs that target these endogenous transmitter systems have been used to improve function after spinal injury. However, individual drugs can have beneficial or deleterious effects in different studies and thus there is little consensus on optimal pharmacological strategies. The variability may be influenced by changes introduced by the type of lesion (complete or partial), time after injury, or the lack of specific ligands that target specific transmitter systems. It is now recognised that these transmitter systems do not necessarily act in isolation, but can interact to evoke additive, inhibitory, or novel metamodulatory effects. Meta interactions mean that differing chemical environments in lesioned spinal cords could influence drug effects. The spinal cord also exhibits injury-induced changes, which could alter the chemical environment and functional properties over time. While they have not been considered in pharmacological approaches to spinal injury, interactive and adaptive changes could influence the effects of spinal lesions and therapeutic interventions. The properties of endogenous transmitter systems in spinal locomotor networks before and after spinal lesions need to be understood, and pharmacological tools that target specific functional aspects need to be developed.

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The novel antagonist 3‐CBW discriminates between kainate receptors expressed on neonatal rat motoneurones and those on dorsal root C‐fibres

Cited by 15 publications

References 37 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

ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function

Pharmacological Approaches to Functional Recovery After Spinal Injury

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