CPP, a new potent and selective NMDA antagonist. Depression of central neuron responses, affinity for [3H]d-AP5 binding sites on brain membranes and anticonvulsant activity

Davies, J.; Evans, Richard H.; Herrling, Paul L.; Jones, Arwel W.; Olverman, Henry J.; Pook, Peter C.K.; Watkins, Johnathan

doi:10.1016/0006-8993(86)90127-7

Cited by 307 publications

(97 citation statements)

References 16 publications

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“…Cross desensitization induced by various excitatory agonists would provide evidence that they activate common receptors. As shown in Figure 5, cross desensitization was observed between Lglutamate (1 mM) and kainic acid (5,M), and between kainic acid (100pM) and acromelic acid A (5puM Depression of kainoid-induced depolarization by CNQX but not by CPP It has been shown that CNQX depresses depolarizing responses to kainate-and quisqualate-type agonists (Honore et al, 1988), and CPP is a selective NMDA antagonist (Davies et al, 1986). Therefore, it was predicted that the kainoidinduced depolarization would not be affected by CPP but depressed effectively by CNQX.…”

Section: Cross Desensitization Between Kainate Derivativesmentioning

confidence: 91%

Novel kainate derivatives: potent depolarizing actions on spinal motoneurones and dorsal root fibres in newborn rats

Ishida

Shinozaki²

1991

British J Pharmacology

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1Neuropharmacological actions of several kainate derivatives (kainoids) were examined for electrophysiological effects in the isolated spinal cord and the dorsal root fibre of the newborn rat. 2 Some kainoids caused depolarization of the motoneurone much more effectively than kainic acid or domoic acid and others were weaker. The rank order of the depolarizing activities of the kainoids tested here is as follows: 442-methoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (MFPA) > acromelic acid A > domoic acid _ 4-(2-hydroxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (HFPA) _ acromelic acid B > kainic acid. 3 In the isolated dorsal root fibre, domoic acid caused the most significant depolarization. There were distinct differences with regard to the rank order of the depolarizing activity between the motoneurone and the dorsal root fibre. The rank order in the dorsal root fibre is domoic acid > acromelic acid B > 5-bromowillardiine _ MFPA > acromelic acid A > HFPA > kainic acid. 4 Significant desensitization of kainate receptors was observed in the isolated dorsal root fibre during prolonged application of L-glutamate, kainate and its derivatives. Cross desensitization was also observed among these excitatory amino acids. Receptors desensitized by kainate did not respond to MFPA, HFPA and acromelic acids, suggesting that these kainate derivatives activated common kainate receptors in the dorsal root fibre.5 In both motoneurones and dorsal root fibres, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) effectively depressed the depolarization induced by kainoids, and neither 3-[(±)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP) nor picrotoxin blocked or affected the depolarization, but there were some differences in pharmacological potencies of glutamate antagonists between both preparations. 6 MFPA, HFPA and acromelic acids should provide valuable pharmacological tools for analysis of physiological functions of excitatory amino acids, in particular, as specific agonists for some subtypes of kainate receptors.

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Section: Cross Desensitization Between Kainate Derivativesmentioning

confidence: 91%

Novel kainate derivatives: potent depolarizing actions on spinal motoneurones and dorsal root fibres in newborn rats

Ishida

Shinozaki²

1991

British J Pharmacology

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“…The first group of selective antagonists of NMDA mediated excitation to be defined were structurally related to agonists and included such compounds as D-2-amino-5-phosphonopentanoate (AP5) (25) and 3-[(±)-2-carboxypiperazin-4-yl]propyl-lphosphonate (CPP) (26), which act as competitive antagonists at the glutamate recognition site. Later, dizocilpine (MK-801) ) that serves as the binding site for competitive antagonists, linker segments to which noncompetitive antagonists bind (S1-M1, S2-M4), an ion channel with three membranespanning segments (M1-M3, where M3 lines the pore) and a pore loop (M2), and a carboxy-terminal cytoplasmic domain.…”

Section: Nmda and Ampa Receptor Antagonistsmentioning

confidence: 99%

Revisiting AMPA Receptors as an Antiepileptic Drug Target

2011

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AMPA receptors are ion channels localized to excitatory synapses in the central nervous system that mediate fast (millisecond time scale) excitatory neurotransmission ( Fig. 1) (1). In excitatory neurons, action potentials evoke the release of glutamate from presynaptic terminals at synapses onto postsynaptic excitatory and inhibitory neurons. Synapses onto excitatory neurons are predominantly located on dendritic spines whereas excitatory synapses onto inhibitory interneurons are located on the aspiny dendritic shafts typical of these cells (2, 3). In either case, the glutamate released from the excitatory neuron axon terminals diffuses across the synaptic cleft and binds to AMPA receptors in the postsynaptic membrane. The AMPA receptors are large multisubunit protein complexes that span the membrane and have an ion-selective central pore that in the absence of glutamate is closed to ion flow. Binding of glutamate causes the AMPA receptors to gate open, which allows cations to flux across the postsynaptic membrane, resulting in a brief depolarization known as the excitatory postsynaptic potential (EPSP). Although AMPA receptors are permeable to sodium, potassium and in some cases also calcium, at resting potential sodium is the main carrier of the depolarizing current. Summation of EPSPs leads to the firing of action potentials by the postsynaptic neuron, completing the transmission of the synaptic signal. Given their role in fast excitatory signaling in the brain, AMPA receptors are a critical component of all neuronal networks. AMPA receptors are as fundamental to brain function as sodium channels but it is important to appreciate the distinction between the two. AMPA receptors mediate synaptic signaling whereas sodium channels are responsible for a neuron's intrinsic excitability. In line with their distinct functions, sodium channels are voltage-gated and they open in response to membrane depolarization. In contrast, AMPA receptors are largely insensitive to membrane potential; as neurotransmitter-gated channels, their opening is controlled by a chemical signal -glutamate, the universal chemical messenger for fast excitatory neurotransmission. The Architecture of AMPA ReceptorsThe cloning of the first AMPA receptor subunit in 1989 enabled the structural analysis of AMPA receptors and a detailed characterization of their physiology and pharmacology (4). It is now well established that there are four AMPA receptor subunits designated GluA1-GluA4 (formerly GluR1-GluR4), each encoded by a separate gene (5). The subunits have a modular organization (Fig. 2) (6, 7). There is a large extracellular aminoterminal domain that is involved in receptor assembly, trafficking and modulation; a ligand-binding domain that serves as the recognition site for agonists (including the natural agonist glutamate) and also represents the binding site for competitive antagonists; a transmembrane domain that forms the ion channel (consisting of three membrane-spanning hydrophobic domains and one intramembranous reentrant loop); and a...

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“…How ever, the poor penetration through the blood-brain barrier of the NMDA antagonists hitherto available (Chapman et aL, 1983) has hindered more detailed pharmacological exploration of the role glutamate plays in cerebral ischemia and has restricted inves tigations almost exclusively to rodents. A number of agents that are selective NMDA receptor antago nists and that cross the blood-brain barrier have re cently been identified (Wong et al, 1986;Davies et al, 1986). In the present study, the effects of pre treatment with one such NMDA antagonist, MK-80 1 (Wong et al, 1986) upon the amount of early ischemic damage after middle cerebral artery occlusion have been examined in anesthetized cats.…”

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confidence: 94%

Protective Effect of the Glutamate Antagonist, MK-801 in Focal Cerebral Ischemia in the Cat

Özyurt

Graham

Woodruff

et al. 1988

J Cereb Blood Flow Metab

360

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Summary:The effects of the glutamate N-methyl-D aspartate (NMDA) receptor antagonist, MK-801, upon ischemic brain damage has been examined in anesthe tized cats. Focal cerebral ischemia was produced by per manent occlusion of one middle cerebral artery and the animals were killed 6 h later. The amount of early isch emic damage was assessed in coronal sections at 16 pre determined stereotactic planes. Pretreatment with MK-801 (5 mg/kg, i.v.). 30 min before occlusion of the Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system. The ac tions of glutamate are mediated via three pharma cologically distinct subtypes of receptor, the no menclature of which reflects the preferred agonist at each receptor subtype viz. the quisqualate-, kainate-, and N-methyl-D-aspartate-(NMDA)-pre ferring receptor (Greenamyre et aL, 1985). Gluta mate has recently been implicated in the patho physiology of cerebral ischemia (Meldrum 1985; Rothman and Olney, 1986). Glutamate itself is neu rotoxic when injected into cerebral tissue (Rothman and Olney, 1986). Cerebral ischemia is associated with a massive increase in extracellular glutamate concentrations (Benveniste et aL, 1984;Hagberg et aL, 1985). Destruction of glutamatergic afferent pathways or intracerebral administration of NMDA receptor antagonists can reduce the early ischemic damage to the hippocampus in cerebral ischemia and the neuronal necrosis which is observed sev eral days after a period of cerebral ischemia or se-

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CPP, a new potent and selective NMDA antagonist. Depression of central neuron responses, affinity for [3H]d-AP5 binding sites on brain membranes and anticonvulsant activity

Cited by 307 publications

References 16 publications

Novel kainate derivatives: potent depolarizing actions on spinal motoneurones and dorsal root fibres in newborn rats

Novel kainate derivatives: potent depolarizing actions on spinal motoneurones and dorsal root fibres in newborn rats

Revisiting AMPA Receptors as an Antiepileptic Drug Target

Protective Effect of the Glutamate Antagonist, MK-801 in Focal Cerebral Ischemia in the Cat

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