CP 465022 hydrochloride

CP 465022 hydrochloride is a potent and selective antagonist of AMPA receptor with IC50 value of 25 nM [1].

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) is an ionotropic transmembrane receptor for glutamate and mediates fast synaptic transmission in the central nervous system. AMPA receptors are oligomeric assemblies of four protein subunits, GluR1-4.

CP 465022 hydrochloride is a noncompetitive and selective AMPA receptor antagonist. In rat cortical neurons, CP-465022 inhibited currents induced by kainate (100 μM) with IC50 value of 25 nM and completely inhibited at concentration up to 3.2 μM. In hNT human teratocarcinoma cells, CP-465022 inhibited kainate-induced currents with IC50 value of 15 nM, which was mediated by AMPA receptors. In cultured cortical neurons stimulated by kainate, CP-465022 dose-dependently inhibited kainate-induced responses by 54% and 88% at 10 nM and 100 nM, respectively [1]. In HEK cells expressing the Nav1.6 channel, CP465022 dose-dependently inhibited Nav1.6-mediated persistent current [2].

In rats after stimulation of Schaeffer collateral/commissural pathway, CP-465022 reversibly inhibited the evoked population spike amplitude in the CA1 region. In pentylenetetrazole-induced seizure rats, CP-465022 dose-dependently reduced the incidence of tonic seizures, clonic seizures and lethality. CP-465022 inhibited vertical and horizontal locomotor activity with ED50 values of 6.6 and 11.9 mg/kg, respectively [3].

References:
[1].  Lazzaro JT, Paternain AV, Lerma J, et al. Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist. Neuropharmacology, 2002, 42(2): 143-153.
[2].  Welch NC, Lin W, Juranka PF, et al. Traditional AMPA receptor antagonists partially block Na v1.6-mediated persistent current. Neuropharmacology, 2008, 55(7): 1165-1171.
[3].  Menniti FS, Buchan AM, Chenard BL, et al. CP-465,022, a selective noncompetitive AMPA receptor antagonist, blocks AMPA receptors but is not neuroprotective in vivo. Stroke, 2003, 34(1): 171-176.

Traditional AMPA receptor antagonists partially block Na v1.6-mediated persistent current.[Pubmed:18687344]

Neuropharmacology. 2008 Dec;55(7):1165-71.

Voltage-gated Na channels and AMPA receptors play key roles in neuronal physiology. Moreover, both channels have been implicated in the pathophysiology of both grey and white matter in a variety of conditions. Dissecting out the roles of these channels requires specific pharmacological tools. In this study we examined the potential non-specific effects on Na(v)1.6 channels of five widely used AMPA receptor blockers. Using whole-cell patch clamp electrophysiology, we identified a TTX-sensitive persistent Na channel current in HEK cells stably expressing the Na(v)1.6 channel. From a holding potential of -120 mV, slow ramp depolarization to +75 mV generated an inward current that peaked at approximately -15 mV. Superfusion of purportedly specific AMPA antagonists, 1-naphthylacetyl spermine, SYM2206, CP465022, GYKI52466, blocked Na(v)1.6-mediated persistent currents in a dose-dependent manner. Each of these AMPA receptor blockers significantly inhibited (to approximately 70% of control levels) the persistent Na current at concentrations routinely used to selectively block AMPA receptors. The AMPA/kainate blocker, NBQX, did not significantly affect persistent Na channel currents. Furthermore, peak transient current was insensitive to NBQX, but was reversibly inhibited by SYM2206, CP465022 and GYKI52466. These results indicate that many commonly used AMPA receptor antagonists have modest but significant blocking effects on the persistent components of Na(v)1.6 channel activity; therefore caution should be exercised when ascribing actions to AMPA receptors based on use of these inhibitors.

CP-465,022, a selective noncompetitive AMPA receptor antagonist, blocks AMPA receptors but is not neuroprotective in vivo.[Pubmed:12511770]

Stroke. 2003 Jan;34(1):171-6.

BACKGROUND AND PURPOSE: Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition has been hypothesized to provide neuroprotective efficacy after cerebral ischemia on the basis of the activity in experimental ischemia models of a variety of compounds with varying selectivity for AMPA over other glutamate receptor subtypes. CP-465,022 is a new, potent, and selective noncompetitive AMPA receptor antagonist. The present study investigated the ability of this compound to reduce neuronal loss after experimental cerebral ischemia to probe the neuroprotective potential of AMPA receptor inhibition. METHODS: To demonstrate that CP-465,022 gains access to the brain, the effects of systemic administration of CP-465,022 were investigated on AMPA receptor-mediated electrophysiological responses in hippocampus and on chemically induced seizures in rats. The compound was then investigated for neuroprotective efficacy in rat global and focal ischemia models at doses demonstrated to be maximally effective in the electrophysiology and seizure models. RESULTS: CP-465,022 potently and efficaciously inhibited AMPA receptor-mediated hippocampal synaptic transmission and the induction of seizures. However, at comparable doses, CP-465,022 failed to prevent CA1 neuron loss after brief global ischemia or to reduce infarct volume after temporary middle cerebral artery occlusion. CONCLUSIONS: Given the high selectivity of CP-465,022 for AMPA over kainate and N-methyl-D-aspartate subtypes of glutamate receptors, the lack of neuroprotective efficacy of the compound calls into question the neuroprotective efficacy of AMPA receptor inhibition after ischemia.

Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist.[Pubmed:11804610]

Neuropharmacology. 2002 Feb;42(2):143-53.

The hypothesis that aberrant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity contributes to epileptogenesis and neurodegeneration has prompted the search for AMPA receptor antagonists as potential therapeutics to treat these conditions. We describe the functional characterization of a novel quinazolin-4-one AMPA receptor antagonist, 3-(2-chloro-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-q uinazolin-4-one (CP-465,022). This compound inhibits AMPA receptor-mediated currents in rat cortical neurons with an IC(50) of 25 nM. Inhibition is noncompetitive with agonist concentration and is not use- or voltage-dependent. CP-465,022 is selective for AMPA over kainate and N-methyl-D-aspartate receptors. However, the compound is found to be equipotent for AMPA receptors composed of different AMPA receptor subunit combinations. This is indicated by the finding that CP-465,022 is equivalently potent for inhibition of AMPA receptor-mediated responses in different types of neurons that express different AMPA receptor subunits. Thus, CP-465,022 provides a new tool to investigate the role of AMPA receptors in physiological and pathophysiological processes.