1-Aminocyclopropane-carboxylic acid reduces NMDA-induced neurodegeneration in vivo

Zapata, Agustín; Capdevila, J.L.; Viu, E.; Trullás, Ramón

doi:10.1097/00001756-199601310-00005

Cited by 13 publications

(2 citation statements)

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“…Unterstützt wird diese Hypothese durch verschiedene neurochemische und klinisch-pharmakologische Untersuchungen, sowie der Tatsache, dass missbräuchlich angewendete NMDA-Antagonisten beim Menschen eine ausgeprägte typisch schizophrene Symptomatik hervorrufen (z.B. Neben der Indikation Depression [26,27] als ein Beispiel für eine psychotische Veränderung wurde auch auf neuroprotektive Effekte überprüft [28,29]. Demzufolge könnten Stimulatoren des NMDA-Rezeptors wie die Glycinagonisten diese Unterfunktion ausgleichen (Tab.…”

Section: Glycin-bindungsstelleunclassified

Teil 2: Therapiekonzepte und neue Rezeptorliganden

Stark

Reichert

Graßmann

2000

Pharmazie in unserer Zeit

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Section: Glycin-bindungsstelleunclassified

Teil 2: Therapiekonzepte und neue Rezeptorliganden

Stark

Reichert

Graßmann

2000

Pharmazie in unserer Zeit

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“…These limiting actions can be overcome by the administration of doses in the 200 -300 mg/kg range which saturate metabolic enzymes and provide the high plasma concentrations required to support entry into the CNS. In this dose range, ACPC has been shown to be neuroprotective in global cerebral ischaemia in the gerbil [80], to be neuroprotective against excitotoxic lesions in vivo [81], and to demonstrate both anxiolytic and antidepressant actions in rat models [82]. The further development of ACPC is currently on hold due to economic considerations.…”

Section: N-methyl-d-aspartate Receptor-associated Glycine Site Partiamentioning

confidence: 99%

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

Wood

Hawkinson

1997

Expert Opinion on Investigational Drugs

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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...

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Functional NMDA Antagonists

Trullás¹

1997

Antidepressants

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1-Aminocyclopropane-carboxylic acid reduces NMDA-induced neurodegeneration in vivo

Cited by 13 publications

References 0 publications

Teil 2: Therapiekonzepte und neue Rezeptorliganden

Teil 2: Therapiekonzepte und neue Rezeptorliganden

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

Functional NMDA Antagonists

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