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.

Tolerance to and Dependence on Alprazolam are Due to Changes in GABAa Receptor Function and Are Independent of Exposure to Experimental Set-up.

The development of tolerance to and dependence on BDZs was investigated by monitoring locomotor activity in mice. Alprazolam (6 mg/kg twice daily s.c.) or solvent were administered over 12 days. The treatment schedule at least 50% BDZ receptor occupancy throughout treatment. Receptor occupancy half-lives were determined to be 2.6 hrs and 4.8 hrs. after cessation of 4 and 12 days of alprazolam administration, respectively. To assess if the tolerance to and dependence on alprazolam were due to repeated exposure of mice to the experimental set-up, some groups of mice were tested repeatedly, while other groups were subjected only to a single exposure. The observed locomotor activity, measured as horizontal activity and total distance travelled, indicated that the development of tolerance and of withdrawal symptoms to alprazolam is not related to repeated exposure of the mice to the experimental set-up, but is due to changes in function of the GABAa receptor.