Disease relevance of LY 293558

• LY293558 significantly increased the duration of ischemia required to produce paraplegia, from 30.5 +/- 15.8 min (mean +/- SD) controls to 50.1 +/- 11.5 in treated animals (p < 0.01) [1].
• Neuroprotective effect of the AMPA receptor antagonist LY-293558 in focal cerebral ischemia in the cat [2].
• CONCLUSIONS: The systemically active AMPA antagonist LY293558, when given at a dose of 5 mg/kg or 15 mg/kg before injury and 10 hours later, does not affect the severity of hypoxic-ischemic brain injury in newborn piglets [3].
• We therefore tested LY293558 in acute migraine [4].
• The effects of the competitive AMPA-KA antagonist LY293558 in two types of experimental pain in human volunteers, brief pain sensations in normal skin, and mechanical allodynia-pinprick hyperalgesia were studied after the injection of intradermal capsaicin [5].

Psychiatry related information on LY 293558

• The effects of LY293558, an AMPA receptor antagonist, on acute and chronic morphine dependence [6].
• When all rats were challenged with morphine (3.0 mg/kg, s.c.) alone on day 11, the locomotor activity of rats previously exposed to LY293558 at 3.0, 1.0, or 0.3 mg/kg--but not at 0.1 mg/kg--was significantly lower than that of rats previously given morphine preceded by vehicle [7].

High impact information on LY 293558

• These effects are prevented by the GluR5 antagonist LY 293558 [8].
• The selective antagonism by LY293558 of GluR5 receptors should allow the determination of the functional role of GluR5 and GluR6 in more complex systems [9].
• In contrast, human embryonic kidney 293 cells expressing GluR6 receptors, although blocked by NBQX, were unaffected by LY293558 at concentrations of < / = 100 microM [9].
• The AMPA antagonist LY293558 improves functional neurological outcome following reversible spinal cord ischemia in rabbits [1].
• Treatment with LY-293558 (15 mg/kg i.v., plus infusion of 7 mg/kg/h) initiated 30 min prior to middle cerebral artery occlusion reduced significantly (p < 0.02) the volume of ischemic damage (from 3,423 +/- 212 mm3 of the cerebral hemisphere in vehicle-treated cats to 2,822 +/- 569 mm3 in LY-293558-treated cats) [2].

Chemical compound and disease context of LY 293558

• It is concluded that antagonism at the AMPA/kainate receptor by GYKI 52466 and LY 293558 beneficially alters HPNS signs but in a manner which is dependent on both the drug and species being studied [10].
• We conducted a randomized, triple-blind, parallel-group, double-dummy, multicentre trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine [4].
• Parenteral, intrathecal, or intraplantar administration of LY293558 was tested against the mechanical hyperalgesia that characterizes the model [11].

Biological context of LY 293558

• In a Phase II study, LY293558 infusions (100% maximally tolerated dose vs. 33% maximally tolerated dose vs. placebo) began 10 min after intradermal injection of 250 microg capsaicin in volar forearm [5].
• An IC50 value of 600 microM was estimated for the competitive antagonist LY293558 and a value of 100 microM estimated for the non-competitive antagonist GYK152466 [12].

Anatomical context of LY 293558

• A selective AMPA antagonist, LY293558, suppresses morphine withdrawal-induced activation of locus coeruleus neurons and behavioral signs of morphine withdrawal [13].
• However, a small number of regions were found to be insensitive to either NBQX or LY-293558, most notably the superior colliculus superficial layer which failed to display significant alterations in glucose use following any concentration of either AMPA antagonist [14].
• The authors examined set-shifting abilities in rats injected with antagonists of N-methyl-D-aspartate (NMDA) receptors (MK801) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (LY293558) into the medial prefrontal cortex (mPFC) [15].
• The greatest reductions in glucose use after NBQX or LY-293558 occurred in primary auditory regions, limbic structures (particularly hippocampal regions and cingulate cortex), neocortex and some thalamic nuclei [14].
• Intrathecal injection of LY293558 (0.5 and 2.0 nmol) produced inhibition of mechanical sensitivity and produced lower extremity motor side effects [11].

Associations of LY 293558 with other chemical compounds

• For LC neurons recorded in vitro in rat brain slices, the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonist, LY293558, showed a greater than 10-fold selectivity for inhibiting the excitatory effects of AMPA vs kainate, and a greater than 30-fold selectivity for inhibiting the excitatory effects of AMPA vs NMDA [13].
• Responses to 30 microM kainate in the presence of LY300168 were virtually abolished by the AMPA and GluR5 kainate receptor competitive antagonist LY293558 (100 microM) [16].
• Cell damage induced by deprivation of oxygen and glucose was prevented by calcium-free medium or by non-N-methyl-D-aspartate glutamate receptor (GluR) antagonists, such as 6-cyano-7-nitroquinoxaline-2,3-dione or LY293558, but not by the voltage-dependent calcium channel blocker, nimodipine, or by the N-methyl-D-aspartate GluR antagonist, MK-801 [17].
• In this study, the novel glutamate receptor antagonist, as its active isomer (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]-decahyd roisoquinoline-3- carboxylic acid ((-)LY293558) and it's +/- racemate (LY215490), was examined for neuroprotectant effects against excitotoxic injury in vitro and in vivo [18].

Gene context of LY 293558

• The NMDA receptor antagonist AP-5 and the AMPA/KA receptor antagonist LY293558 were infused directly into the core or shell [19].
• We studied the effects of intrathecal LY293558, a competitive non-N-methyl-D-aspartate excitatory amino acid receptor antagonist, on motor and sensory function in rats to determine whether drugs blocking these receptors could potentially be used as alternative agents to local anesthetics for spinal anesthesia [20].
• LY293558, a novel, systemically active, competitive AMPA receptor antagonist and the NMDA receptor antagonists, MK-801 and/or LY235959, were evaluated in tolerant or dependent CD-1 mice [6].
• The Effect of the AMPA/Kainate Receptor Antagonist LY293558 in a Rat Model of Postoperative Pain [11].

Analytical, diagnostic and therapeutic context of LY 293558

• Effect of intrathecal non-NMDA EAA receptor antagonist LY293558 in rats: a new class of drugs for spinal anesthesia [20].
• METHODS: Rats were tested before and 15-240 min after intrathecal injection of 5 nmol (in 10 microl) LY293558 [20].
• METHODS: Brief intravenous infusions of the competitive AMPA-KA antagonist LY293558 were given to 25 healthy volunteers to examine acute toxicity and analgesic effects [5].
• Neither LY293558 nor MK-801 produced analgesia or altered the ED50 value of morphine [6].

References