Effects of the N-methyl-D-aspartate receptor antagonist perzinfotel [EAA-090; [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity.
Perzinfotel [EAA-090; [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] is a selective, competitive N-methyl-D-aspartate (NMDA) receptor antagonist with high affinity for the glutamate site. The current study evaluated whether perzinfotel would have antinociceptive effects or block thermal hypersensitivity associated with the administration of chemical irritants in rats. Perzinfotel lacked antinociceptive effects but dose- and time-dependently blocked prostaglandin E(2) (PGE(2))- and capsaicin-induced thermal hypersensitivity in a warm-water tail-withdrawal assay in rats. Doses of 10 mg/kg intraperitoneal or 100 mg/kg oral blocked PGE(2)-induced hypersensitivity by 60 to 80%. The magnitude of reversal was greater than other negative modulators of the NMDA receptor studied, such as uncompetitive channel blockers (e.g., memantine, dizocilpine, and ketamine), a NR2B selective antagonist (e.g., ifenprodil), and other glutamate antagonists [e.g., selfotel, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP-39653)], up to doses that suppressed operant rates of responding. In contrast to other negative modulators of the NMDA receptor studied, which typically decreased operant rates of responding at doses that lacked antinociceptive effects, perzinfotel did not modify response rates at doses that blocked irritant-induced thermal hypersensitivity. Collectively, these studies demonstrate that perzinfotel has therapeutic ratios for effectiveness versus adverse effects superior to those seen with other competitive and uncompetitive NMDA receptor antagonists studied.
Brandt
Michael R
MR
Neuroscience Discovery Research, Wyeth Research, Princeton, New Jersey, USA. mbrandt4@prdus.jnj.com
Cummons
Terri A
TA
Potestio
Lisa
L
Sukoff
Stacey J
SJ
Rosenzweig-Lipson
Sharon
S
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D053961:Azabicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D015232:Dinoprostone / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006358:Hot Temperature; D008297:Male; D009020:Morphine / Q000494:pharmacology; D063065:Organophosphonates; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000700:Analgesics; D053961:Azabicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; D063065:Organophosphonates; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; C110623:EAA-090; D015232:Dinoprostone