Phosphonate quinoxalinedione AMPA antagonists
In the Western world, over 350,000 deaths and $30 billion in medical costs are attributed annually to stroke. Head and spinal cord trauma cause an estimated 250,000 deaths annually and result in medical costs of $15 billion. Although stroke and head/spinal cord trauma are leading causes of disability and death in humans, no adequate neuroprotective treatment is available. Glutamate antagonists derived from the quinoxa-linedione scaffold are as drug candidates for neuroprotection in stroke and trauma. Quinoxalinedione derivatives such as 2,3-dihydroxy-6- nitro-7-sulfamoylbenzo(f)quinoxaline and 6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione failed clinical trials because of insolu-bility and resulting nephrotoxicity. Introduction of a phosphonate group into the quinoxalinedione skeleton improves solubility and leaves potency for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor unchanged. Phosphonate quinoxalinedione derivatives ZK202000 and ZK200775 protected rodent brain against sequelae of permanent occlusion of the middle cerebral artery and head trauma. No major deleterious effects on motor coordination, cardiovascular, or respiratory systems were detected in doses required for neuroprotection. No psychotomimetic and no neurotoxic side effects, typical for N-methyl-D-aspartate antagonists, were observed following treatment with phosphonate quinoxalinediones.
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ABSTRACT: Accumulated data suggest that N-methyl-D-aspartate (NMDA) receptors are involved in the reinforcing properties of nicotine. However, less is known about the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptors in this context.
To study the effect of the novel systemically administered AMPA receptor antagonist ZK200775 ([1,2,3,4-tetrahydro-7-morpholinyl-2,3-dioxo-6-(fluoromethyl) quinoxalin-1-yl] methylphosphonate) on nicotine-induced dopamine (DA) release in the nucleus accumbens (NAcc) and nicotine-stimulated locomotor activity (LMA) and particularly the relative role of NMDA and AMPA receptors in nicotine-stimulated DA release and LMA.
Male Wistar rats were administered ZK200775, CGP39551 or NBQX 30 min prior to nicotine and DA release and LMA was measured using in vivo microdialysis or photocell equipped activity boxes. Glutamate-produced neurotoxicity in cultured brain cells and binding assays were performed to determine the glutamate receptor subtype selectivity and affinity to nicotine receptors of ZK200775, respectively.
ZK200775 (3.0 but not 1.5 or 6.0 mg/kg) significantly decreased the nicotine-induced (0.6 mg/kg) DA release in the NAcc and nicotine-stimulated LMA. ZK200775 (1.5, 3.0, 6.0 mg/kg) alone influenced neither DA release nor LMA. ZK200775 showed 34-fold selectivity for AMPA receptors compared to NMDA receptors and no affinity to nicotine receptors. The NMDA receptor antagonist CGP39551 (10 mg/kg) significantly decreased both the nicotine-induced DA release and nicotine-stimulated LMA whereas the AMPA receptor antagonist NBQX (10 mg/kg) had no effect. Notably, CGP39551 and ZK200775 (3.0 mg/kg) displayed a different pattern in inhibition of nicotine-induced DA release.
Both NMDA- and AMPA receptors are involved in nicotine's dependence-producing properties, although in a spatiotemporally differential manner.
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