N-methyl-D-aspartate antagonists for stroke and head trauma

Abstract

The N-methyl-D-aspartate (NMDA) receptor is a ligand-gated ion channel which is widely distributed in the central nervous system (CNS), and which mediates most of the fast excitatory neuronal transmission in the CNS. As with other ligand-gated ion channels, the NMDA receptor is a macromolecular complex which possesses a number of intricate regulatory sites within and around a central ion channel. The key regulatory components for which prototypic antagonists have been developed are the competitive NMDA antagonist binding site, the non-competitive NMDA antagonist binding site within the ion channel, and the NMDA receptor-associated glycine antagonist site. The binding domains for each of these binding sites possess discrete and non-overlapping SAR with regard to the chemical series developed to date. The potential utility of NMDA antagonists in the treatment of stroke and traumatic brain injury was investigated soon after the synthesis of the first bioavailable NMDA antagonists. Efficacy in preclinical models was demonstrated with both competitive and non-competitive NMDA antagonists. However, preclinical testing also revealed potentially clinically-limiting side-effects which included phencyclidine (PCP)-like actions indicative of possible psychotomimetic activity, cerebral vacuolisation of limbic cortical neurones, low therapeutic indices relative to incapacitating motor side-effects and, in the case of non-competitive antagonists, hypertension. These limitations have led to the design of clinical trials that should define the therapeutic index for this type of compound in humans. Currently, the first competitive antagonist to enter clinical trials, selfotel, is on hold, while D-CPPene is still in development. The non-competitive antagonist, aptiganel, is currently in Phase III clinical trials and its therapeutic efficacy and index should be defined in 1997 and 1998. The well-defined limitations of competitive and non-competitive NMDA antagonists have been a key impetus in the investigation of alternative approaches to modulating the NMDA receptor complex. In the case of glycine site antagonists, these compounds have been shown in preclinical studies to be devoid of PCP-like actions and the neuronal vacuolisation associated with the competitive and non-competitive NMDA antagonists. This has induced the development of a number of chemical series with at least three compounds currently in Phase I and II clinical trials. These include ACEA 1021, GV150526A and ZD9379. Clinical efficacies and therapeutic indices of these compounds should be defined in 1998 and 1999. An alternative approach using a partial agonist of the glycine site (1-aminocyclopropane-carboxylic acid, ACPC) has been halted in Phase I. Another approach which has led to the development of NMDA receptor antagonists, selective for the NMDA receptor subunits 1A/2B (NR1A/2B subtype), was the discovery in early studies of the neuroprotective actions of ifenprodil. Structural analogues include eliprodil, CP-101,606 and lubeluzole. In the cases of eliprodil...

On the Hypes and Falls in Neuroprotection: Targeting the NMDA Receptor

“…As glutamate is an essential mediator of neuronal cell death in this model, specific receptor blockers are thought to selectively interrupt postischemic excitotoxicity. As a consequence, high hopes had been associated with the design of novel NMDA receptor antagonists, including selfotel, aptiganel, and gavestinel (Omae and others 1996;Wood and Hawkinson 1997;Farin and Marshall 2004;Wood 2005). The efficient chemical design of these antagonists yielded excellent ligand binding properties at the glycine site of the NMDA receptor.…”

Glutamatergic autoencephalitides: an emerging field

“…Because of this, a significant amount of time and effort has gone into developing clinically useful NMDAR antagonists. However, while many of these antagonists successfully reduced or eliminated damage in animal models, all failed in clinical trials, in large part due to their unacceptable side effects, including psychosis (Wood PL, 1997; Lai et al, 2011). This double-edged sword demonstrates the importance of carefully calibrated NMDAergic activity in normal neurologic function.…”

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

“…Physiologically, a blockade of at least one of these sites terminates the channel opening of the NMDA receptor to prevent Ca 2+ influx. However, several studies have demonstrated that a compound which would act as a glycine site antagonist might be superior to an NMDA competitive antagonist and a channel blocker with respect to the therapeutic index [13][14][15][16][17][18][19].…”