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

Abstract

Effects of the N-Methyl-D-aspartate Receptor AntagonistPerzinfotel [2][3][4][5][6][7][8] ABSTRACT Perzinfotel [2][3][4][5][6][7][8].0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] is a selective, competitive Nmethyl-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.Excitatory amino acids acting at NMDA receptors play a role in both acute and chronic pain. Increases in afferent input and glutamate release within the spinal cord have been observed after peripheral injection of an irritant (e.g., carrageenan) or tissue injury (Sluka and Westlund, 1993;Kawamata and Omote, 1996;Dickenson et al., 1997). Repeated stimulation of primary afferent fibers can progressively increase the magnitude and duration of action potentials in spinal cord (often termed "windup"), which can lead to central sensitization (Ma and Woolf, 1995). This neuronal hyperexcitability manifests itself in a lowered threshold to evoked activity (i.e., hyperalgesia), an expansion of receptive fields (i.e., secondary hypersensitivity), and an ability of non-noxious input to evoke neuronal activity (i.e., allodynia). In preclinical studies, NMDA receptor antagonists reverse neuronal hyperexcitability and reverse hypersensitivity in several inflammatory and neuropathic animal pain models associated with various pathophysiologic mechanisms (Mao et al., 1993;Chaplan et al., 1997;Suzuki et al., 2001). In clinical studies, NMDA receptor antagonists, such as ketamine and dextromethorphan, reduce windup pain, spontaneous pain, hyperalgesia, and allodynia in patients with postherpetic neuralgia pain, phantom ...

Prodrugs of Perzinfotel with Improved Oral Bioavailability

“…It is selective for the NMDA receptor, showing no significant affinity at over 60 other receptor, enzyme, and ion channel binding sites. − Previous studies demonstrated 1 to be efficacious in a variety of pain models . However, 1 demonstrates low bioavailability following oral administration . In the current study, we prepared and evaluated oxymethylene-spaced prodrugs of 1 to determine whether they would show improved oral bioavailability.…”

“…We previously described perzinfotel ( 1 , EAA-090, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid) as a potent, competitive NMDA receptor antagonist. It is selective for the NMDA receptor, showing no significant affinity at over 60 other receptor, enzyme, and ion channel binding sites. − Previous studies demonstrated 1 to be efficacious in a variety of pain models . However, 1 demonstrates low bioavailability following oral administration .…”

Lack of efficacy of NMDA receptor-NR2B selective antagonists in the R6/2 model of Huntington disease

“…. In preliminary testing, perzinfotel had undetectable blood levels with all routes of administration but was evaluated because of prior reports suggesting efficacy in models of ischemia and pain (Kinney et al, 1998; Sun et al, 2004; Brandt et al, 2005). Dose was chosen on the basis of prior literature.…”

Squaramides as Bioisosteres in Contemporary Drug Design

“…Perzinfotel was subsequently found to be efficacious in models of pain, selectively ameliorating glutamate-induced neurotoxicosis and inhibiting both thermal and tactile hypersensitivities induced by prostaglandin E 2 , capsaicin, as well as spinal nerve lesions . It is also highly selective toward NMDA R1/R2A receptors over NR1/NR2B and NR1/NR2C, exhibiting no significant affinity toward the binding sites of an array of other enzymes, receptors, and ion channels. ,− Furthermore, in animal toxicity models and in human Phase I trials it was found to be exceptionally safe. , Perzinfotel has additionally found use in veterinary medicine, improving anesthetic safety in cats and dogs by reducing anesthetic requirements and improving cardiovascular function during anesthesia. − In 2009, poor bioavailability of perzinfotel led Wyeth to develop a phosphodiester prodrug ( 124 ;see Figure ), which exhibited ∼2.5-fold greater systemic exposure of the parent drug at 10 mg/kg administered orally, compared to a 30 mg/kg dose of perzinfotel . Despite these promising results, development of perzinfotel was eventually discontinued.…”