Bertrand Leo Chenard

CP-101,606, a potent neuroprotectant selective for forebrain neurons

The neuroprotective activity of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606), an N-methyl-D-aspartate (NMDA) receptor antagonist structurally similar to ((+/-)-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-++ +piperidineethanol (ifenprodil), was investigated in neurons in primary culture. CP-101,606 potently and efficaciously protected hippocampal neurons from glutamate toxicity but was > 900-fold less effective for cerebellar granule neurons. The neuroprotective activity in the hippocampal neurons is mediated through a high affinity binding site distinct from the agonist and thienylcyclohexylpiperidine (TCP) binding sites of the NMDA receptor. Autoradiography indicates the CP-101,606 binding site is localized in forebrain, most notably in hippocampus and the outer layers of cortex. The functional selectivity for hippocampal neurons, forebrain localization of binding sites, and structural relation to ifenprodil suggest that CP-101,606 is an NMDA antagonist highly selective for NR2B subunit containing receptors.

Atropisomeric quinazolin-4-one derivatives are potent noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists

Piriqualone (1) was found to be an antagonist of AMPA receptors. Structure activity optimization was conducted on each of the three rings in 1 to afford a series of potent and selective antagonists. The sterically crowded environment surrounding the N-3 aryl group provided sufficient thermal stability for atropisomers to be isolated. Separation of these atropisomers resulted in the identification of (+)-38 (CP-465,022), a compound that binds to the AMPA receptor with high affinity (IC50 = 36 nM) and displays potent anticonvulsant activity.

CP-101,606, an NR2B subunit selective NMDA receptor antagonist, inhibits NMDA and injury induced c-fos expression and cortical spreading depression in rodents.

(1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606) is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors containing the NR2B subunit. This compound was used to investigate the role of NR2B containing receptors in three responses to NMDA receptor activation in vivo. In mouse, CP-101,606 completely inhibited increases in fos-like immunoreactivity in dentate gyrus caused by a subconvulsant intraperitoneal dose of NMDA. In rat, the compound completely blocked cortical c-fos mRNA induction following focal injury in parietal cortex and the initiation and propagation of electrically induced cortical spreading depression. Inhibition of these responses by CP-101,606 indicates that c-fos induction and cortical spreading depression are dependent on activation of NMDA receptors containing the NR2B subunit. Since NMDA receptor dependent c-fos induction and cortical spreading depression may contribute to neuron loss after focal CNS injury, inhibition of these responses by CP-101,606 may contribute to the neuroprotective efficacy of the compound.

Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist

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-quinazolin-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.

CP-465,022, a Selective Noncompetitive AMPA Receptor Antagonist, Blocks AMPA Receptors but Is Not Neuroprotective In Vivo

Background and Purpose— &agr;-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.

CP-101,606: An NR2B-Selective NMDA Receptor Antagonist

Glutamate and aspartate play dual roles in the central nervous system as essential amino acids and the principal excitatory neurotransmitters. The theory of excitotoxicity presents the paradoxical view that these excitatory amino acids may also become endogenous neurotoxins any time the brain’s energy homeostasis is compromised (16,23,42,59). Cerebral ischemia and traumatic brain injury result in acute energy depletion and cellular depolarization. This triggers a dramatic increase in extracellular glutamate levels (10,11) due to presynaptic glutamate release and/or reversal of neuronal and glial glutamate transporters (63,64). The result is a prolonged overactivation of glutamate receptors which, through an incompletely understood cascade of events, leads to neuron death. Glutamate receptor activity is also hypothesized to play a role in the neuron death associated with chronic neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease. In these latter conditions, subtle but chronic deregulation in neuronal energy metabolism renders neurons susceptible to excitotoxicity from physiological glutamate receptor activity (1,23,36). Given the premise of excitotoxicity as a central event in neuron loss associated with both acute and chronic neurodegenerative conditions, glutamate-receptor inhibition has been an aggressively pursued therapeutic strategy to treat these conditions. There are four major classes of glutamate receptors: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate, and metabotropic (2). Of these, NMDA receptors appears to be especially important to the excitotoxic process. The NMDA receptor is an ion channel gated by synaptically released glutamate in the presence of the coagonist glycine (29,32) and concomitant depolarization (38). The NMDA receptor is permeable to Na and Ca; it is Ca influx through the receptor that

Methaqualone derivatives are potent noncompetitive AMPA receptor antagonists

Quinazolin-4-one derivatives of methaqualone substituted at C-2 define a new class of noncompetitive antagonists at AMPA receptors.

A short synthesis of GYKI 52466

Abstract The synthesis of GYKI 52466 has been achieved in a short six step sequence which proceeds in an overall yield of 11.5%.

Oxindole N-Methyl-D-Aspartate (NMDA) antagonists

Abstract Replacement of the phenol group in non-competitive NMDA antagonist ifenprodil with oxindole results in a new series of ′non-traditional′ NMDA antagonists. In combination with threo relative stereochemistry, improved NMDA antagonist potency and selectivity may be achieved.