A novel class of amino-alkylcyclohexanes as uncompetitive, fast, voltage-dependent, N-methyl-D-aspartate (NMDA) receptor antagonists – in vitro characterization

  title={A novel class of amino-alkylcyclohexanes as uncompetitive, fast, voltage-dependent, N-methyl-D-aspartate (NMDA) receptor antagonists – in vitro characterization},
  author={K. Gilling and C. Jatzke and C. Wollenburg and M. Vanejevs and V. Kauss and A. Jirgensons and C. Parsons},
  journal={Journal of Neural Transmission},
SummaryThe fact that potent NMDA receptor channel blockers produce phencyclidine-like psychotropic symptoms in man and rodents implies that uncompetitive antagonism of NMDA receptors may not be a promising therapeutic approach. However, recent data indicate that agents with moderate affinity such as memantine and neramexane (MRZ 2/579) are useful therapeutics due to their strong voltage-dependency and rapid unblocking kinetics. Merz has developed a series of novel uncompetitive NMDA receptor… Expand
Pharmacological and Electrophysiological Characterization of Novel NMDA Receptor Antagonists.
This work reports the synthesis and pharmacological and electrophysiological evaluation of new N-methyl-d-aspartic acid receptor (NMDAR) channel blocking antagonists featuring polycyclic scaffolds, showing properties comparable to those of memantine, a clinically approved NMDAR antagonist. Expand
Influence of external magnesium ions on the NMDA receptor channel block by different types of organic cations
Diversity in Mg(2+) effects on the NMDAR channel block by different organic cations reported herein likely reflects interaction of N MDAR channel blockers with additional binding site(s) and suggests that individual analysis in the presence of Mg (2+) is required for newly developed NMD AR channel blocking drugs. Expand
Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors.
The review covers the evolution of research in this field over the last 25 years and proposes assigning drugs to 18 categories according to their mechanism(s) of action. Expand
Neuropharmacology of Vestibular System Disorders
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Clinical trials are now underway to evaluate the efficacy of N-methyl-d-aspartate (NMDA) and dopamine D(2) antagonists, selective serotonin reuptake inhibitors (SSRIs), γ-aminobutyric acid (GABA) agonists and zinc dietary supplements, as well as animal behavioral studies suggest that GABA transaminase inhibitors and potassium channel modulators can suppress tinnitus. Expand
Synthesis of Natural Product-Based Probes for the Central Nervous System
iii Acknowledgements iv Table of
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This study applies a variety of ligand- and structure-based assessment techniques used in standard drug discovery analyses to the deep learning-generated compounds, and presents twelve candidate antagonists that are not available in existing chemical databases to provide an example of what this type of workflow can achieve. Expand


Amino-alkyl-cyclohexanes are novel uncompetitive NMDA receptor antagonists with strong voltage-dependency and fast blocking kinetics: in vitro and in vivo characterization
The present study characterized the in vitro NMDA receptor antagonistic properties of novel amino-alkyl-cyclohexane derivatives and compared these effects with their ability to block excitotoxicity in vitro and MES-induced convulsions in vivo, indicating similar access of most compounds to the CNS. Expand
Amino-alkyl-cyclohexanes as a novel class of uncompetitive NMDA receptor antagonists.
The present review describes the rational for developing amino-alkyl-cyclohexanes, as new uncompetitive NMDA receptor antagonists based on positive experience with memantine, which has been used clinically for many years for the treatment of neurodegenerative dementia. Expand
Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data
Preclinical data on memantine is summarized to provide evidence that it is indeed possible to develop clinically well tolerated NMDA receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies in developing compounds with similar properties to memantine. Expand
NMDA antagonists and neuropathic pain--multiple drug targets and multiple uses.
Agents that are selective for receptors that include the NR2B subunit preclinically have a substantially better profile for treating neuropathic pain than do current NMDA antagonists; some emerging clinical evidence supports this view. Expand
The N-methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications.
The NR2B subunit of the NMDA receptor has been implicated in modulating functions such as learning, memory processing, pain perception, and feeding behaviors, as well as being involved in a number of human disorders. Expand
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This presentation is an attempt to critically review preclinical and scarce clinical experience in the development of new NMDA receptor antagonists as neuroprotective agents according to the following scheme: rational, preclinical findings in animal models and finally clinical experience if available. Expand
Mechanism of action of memantine.
The unusual therapeutic utility of memantine probably results from inhibitory mechanisms shared with ketamine, combined with actions specific to memantine, including effects on gating of blocked channels and binding of Memantine to two sites on NMDA receptors. Expand
NMDA receptors as targets for drug action in neuropathic pain.
  • C. Parsons
  • Medicine
  • European journal of pharmacology
  • 2001
Peripheral NMDA receptors offer a very attractive target for NMDA receptor antagonists that do not cross the blood brain barrier in inflammatory and visceral pain and such agents might be predicted to be devoid of CNS side effects at doses producing powerful antinociception at peripheralNMDA receptors. Expand
The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence
It is suggested that glutamate receptors of the N‐methyl‐D‐aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner in Alzheimer's disease, and memantine would be expected to improve both symptoms (cognition) and to slow down disease progression because it takes over the physiological function of magnesium. Expand
Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond
  • S. Lipton
  • Chemistry, Medicine
  • Nature Reviews Drug Discovery
  • 2006
The molecular basis for memantine efficacy in neurological diseases that are mediated, at least in part, by overactivation of NMDARs, producing excessive Ca2+ influx through the receptor's associated ion channel and consequent free-radical formation is reviewed. Expand