YM872: A Selective, Potent and Highly Water‐Soluble α‐Amino‐3‐Hydroxy‐5‐Methylisoxazole‐4‐Propionic Acid Receptor Antagonist

Takahashi, M; Kohara, Atsuyuki; Shishikura, Jun-ichi; Kawasaki-Yatsugi, Sachiko; Ni, Jian; Yatsugi, Shin-ichi; Sakamoto, Shuichi; Okada, Masamichi; Shimizu‐Sasamata, Masao; Yamaguchi, Tokio

doi:10.1111/j.1527-3458.2002.tb00232.x

Cited by 44 publications

(30 citation statements)

References 48 publications

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“…73 Moreover, recent reports have suggested both the competitive AMPAR antagonist YM872 (12, Fig. 4), 74 as well as the noncompetitive antagonist GYKI 53784 (14, Fig. 5), 75 as potential drugs.…”

Section: Ampar Antagonistsmentioning

confidence: 98%

AMPA receptor ligands: Synthetic and pharmacological studies of polyamines and polyamine toxins

Strømgaard

Mellor

2004

Medicinal Research Reviews

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Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine-based ligands, particularly polyamine toxins, are unique as they selectively block Ca2+ -permeable AMPARs. Indeed, endogenous intracellular polyamines are known to modulate the function of these receptors in vivo. In this study, recent developments in the medicinal chemistry of polyamine-based ligands are given, particularly focusing on the use of solid-phase synthesis (SPS) as a tool for the facile generation of libraries of polyamine toxin analogues. Moreover, the recent development of highly potent and very selective AMPAR ligands is described. Additionally, we provide a detailed account on the mechanism and site of action of AMPAR blockade by polyamine-based ligands, including examples of how these ligands are used as tools to study AMPAR, and a comparison with their action on other ionotropic receptors.

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Section: Ampar Antagonistsmentioning

confidence: 98%

AMPA receptor ligands: Synthetic and pharmacological studies of polyamines and polyamine toxins

Strømgaard

Mellor

2004

Medicinal Research Reviews

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“…It is of interest that, while AMPA antagonists showed neuroprotective efficacy in certain preclinical settings of both focal and global cerebral ischemia Gill, 1994;Xue et al, 1994;Lees, 2000;Takahashi et al, 2002), the successful completion of larger clinical trials has not been reported. In a phase II double-blind multicenter trial (Elting et al, 2002), the AMPA antagonist ZK200755, when administered in a higher dose, produced a marked transient worsening of the NIHSS score attributable to a depression of consciousness (stupor or coma).…”

Section: Ampa Receptor Antagonismmentioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

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“…These include calcium channel blockade [23], calcium chelation [24], free-radical trapping [25], gamma-aminobutyric acid (GABA) and serotonin agonism [26, 27], and alpha-amino-5-hydroxy-3-methyl-4-isoxazole propionic acid (AMPA) and N-methyl- d -aspartate (NMDA) receptor antagonism [28, 29]. While a large number of neuroprotective agents have been shown to successfully reduce infarct size in animal models of focal and global ischaemia, neuroprotective compounds administered as monotherapy have failed to demonstrate efficacy for the treatment of AIS in phase III clinical trials in humans [15, 30, 31].…”

Section: Neuroprotection: Aims and Approachesmentioning

confidence: 99%

The Past and Future of Neuroprotection in Cerebral Ischaemic Stroke

Shuaib

Hussain²

2007

Eur Neurol

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Following the realization that cerebral tissue may survive for hours after an ischaemic insult, several agents with neuroprotective properties in small-animal models of cerebral ischaemia have been tested in patients with acute ischaemic stroke (AIS). Initial attempts at translating the positive effects of these agents from animal models to patients were unsuccessful, possibly as a result of poorly planned experiments in models of ischaemia, and/or clinical trials of AIS that were not optimized to show a positive effect. Newer neuroprotective agents that are believed to act later in the ischaemic cascade may offer a greater chance of success. However, before these agents can be introduced into clinical practice they must undergo assessment in rodent and large-animal models of AIS and, in particular, the dose-response relationship and the treatment time window should be defined. This should be followed by evaluation in carefully designed clinical trials of adequate power, involving subjects receiving an appropriate dose within an optimum time window following the onset of symptoms. There is hope that such careful strategies may guide continued progress in neuroprotective drug development.

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YM872: A Selective, Potent and Highly Water‐Soluble α‐Amino‐3‐Hydroxy‐5‐Methylisoxazole‐4‐Propionic Acid Receptor Antagonist

Cited by 44 publications

References 48 publications

AMPA receptor ligands: Synthetic and pharmacological studies of polyamines and polyamine toxins

AMPA receptor ligands: Synthetic and pharmacological studies of polyamines and polyamine toxins

Neuroprotection for ischemic stroke: Past, present and future

The Past and Future of Neuroprotection in Cerebral Ischaemic Stroke

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