Neuroprotection by novel antagonists at the NMDA receptor channel and glycineB sites.
Glutamate may act via an N-methyl-D-Aspartate (NMDA)-sensitive receptor site to destroy cholinergic neurons within the nucleus basalis magnocellularis in age-associated neurodegenerative diseases. Multiple interesting properties of the NMDA receptor are relevant to its excitotoxic actions, e.g., glutamate is ineffective unless a glycine (gly) modulatory site is also occupied. Thus, the antagonism of glutamate receptor-related toxicity by blockade of either the NMDA-sensitive recognition site or the gly binding site may therefore have therapeutic applications. The current study investigated the ability of four novel noncompetitive antagonists at these two sites: one NMDA open channel antagonist (MRZ 2/579: 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride), and three glyB receptor antagonists (MRZ 2/570: 8-bromo-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline salt; MRZ 2/57: 8-fluoro-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline; MRZ 2/576: 8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline) administered acutely, to provide neuroprotection from a NMDA receptor agonist within the nucleus basalis magnocellularis of young rats. Injection of NMDA into the nucleus basalis magnocellularis significantly decreased cortical choline acetyltransferase activity. Acute administration (i.p.) of MRZ 2/579, 2/570, 2/571 and 2/576 provided significant neuroprotection from NMDA.
Wenk
G L
GL
Arizona Research Laboratories, Division of Neural Systems, Memory and Aging, University of Arizona, Tucson 85724, USA. gary@nsma.arizona.edu
Baker
L M
LM
Stoehr
J D
JD
Hauss-Wegrzyniak
B
B
Danysz
W
W
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D003517:Cyclopentanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D051381:Rats; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013377:Substantia Innominata / Q000187:drug effects* / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors
D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C114144:neramexane; D013385:Succinate Dehydrogenase; D000109:Acetylcholine; C015392:3-nitropropionic acid