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Special Issue "NMDA Receptor Antagonists for Treatment of CNS Disorders"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 December 2012)

Special Issue Editor

Guest Editor
Prof. Dr. Adeboye Adejare (Website)

Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 S. 43rd Street, Philadelphia, PA 19104, USA
Interests: drug targeting; mechanisms of neurodegeneration; chemistry of fluoroaromatic compounds; pharmaceutical profiling

Special Issue Information

Dear Colleagues,

Glutamate receptors are known to play key roles in the CNS. Over-activity of these receptors which may be due to several factors including over-expression and higher levels of glutamate, has been linked to several CNS disorders. Glutamate receptors can broadly be divided into metabotropic and ionotropic. The ionotropic receptors have been further sub classified into three mainly based on agonists, namely, N-methyl-D- aspartic acid (NMDA), Kaininc acid and (alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid) AMPA. While all these receptors are possible drug targets, the NMDA receptor has been particularly targeted for drug discovery efforts. These efforts have led to memantine, a USA FDA approved drug for treatment of Alzheimer’s disease. Other drugs acting at NMDA receptors are being examined for various disorders, from severe depression to drug abuse, to treatment of memory and learning issues in neurofibromatosis type 1 (NF1). The goal of this special issue is to examine current efforts in CNS drug discovery through this receptor.

Prof. Dr. Adeboye Adejare
Guest Editor

Keywords

  • glutamate
  • NMDA antagonist
  • CNS drug discovery
  • Alzheimer’s disease
  • neuropathic pain
  • drug addiction
  • memory and learning
  • ionotropic receptors

Published Papers (5 papers)

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Research

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Open AccessArticle Toxicity Studies on Novel N-Substituted Bicyclo-Heptan-2-Amines at NMDA Receptors
Pharmaceuticals 2013, 6(4), 536-545; doi:10.3390/ph6040536
Received: 25 January 2013 / Revised: 9 April 2013 / Accepted: 9 April 2013 / Published: 12 April 2013
Cited by 3 | PDF Full-text (1046 KB) | HTML Full-text | XML Full-text
Abstract
Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the [...] Read more.
Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the toxic effects of the compounds as compared with memantine, an NMDA receptor antagonist that is FDA approved for treatment of Alzheimer’s disease, by testing these compounds on two cell lines: MDCK (to mimic blood brain barrier) and N2a (a neuronal cell line). The compounds showed toxicity profiles similar to those of memantine i.e., dose dependence above 100 μM and IC50 values above 150 μM for each cell line. It is known that the serum level of memantine under therapeutic conditions in patients is about 1 µM, indicting these compounds could have acceptable therapeutic indexes. 2-Phenyl-N-(2-(piperidin-1-yl) ethyl)bicyclo[2.2.1]heptan-2-amine (5a) was found to possess acceptable toxicity profiles in both cell lines. Interestingly, this was the compound identified as a good lead in our previous studies based on binding and anticonvulsant (MES) activity studies. It has thus emerged as an excellent lead compound for further studies. Full article
(This article belongs to the Special Issue NMDA Receptor Antagonists for Treatment of CNS Disorders)
Figures

Open AccessArticle Interactions of a Dopamine D1 Receptor Agonist with Glutamate NMDA Receptor Antagonists on the Volitional Consumption of Ethanol by the mHEP Rat
Pharmaceuticals 2013, 6(4), 469-479; doi:10.3390/ph6040469
Received: 25 December 2012 / Revised: 23 February 2013 / Accepted: 15 March 2013 / Published: 26 March 2013
PDF Full-text (212 KB) | HTML Full-text | XML Full-text
Abstract
Stimulation of the dopamine D1 receptor is reported to cause the phosphorylation of DARPP-32 at the thre34 position and activates the protein. If intracellular Ca2+ is increased, such as after activation of the glutamate NMDA receptor, calcineurin activity increases and the [...] Read more.
Stimulation of the dopamine D1 receptor is reported to cause the phosphorylation of DARPP-32 at the thre34 position and activates the protein. If intracellular Ca2+ is increased, such as after activation of the glutamate NMDA receptor, calcineurin activity increases and the phosphates will be removed. This balance of phosphorylation control suggests that a D1 receptor agonist and a NMDA glutamate receptor antagonist should have additive or synergistic actions to increase activated DARPP-32 and consequent behavioral effects. This hypothesis was tested in a volitional consumption of ethanol model: the selectively bred Myers’ high ethanol preferring (mHEP) rat. A 3-day baseline period was followed by 3-days of twice daily injections of drug(s) or vehicle(s) and then a 3-day post-treatment period. Vehicle, the D1 agonist SKF 38393, the non-competitive NMDA receptor antagonist memantine, or their combination were injected 2 h before and after lights out. The combination of 5.0 mg/kg SKF 38393 with either 3.0 or 10 mg/kg memantine did not produce an additive or synergistic effect. For example, 5.0 mg/kg SKF reduced consumption of ethanol by 27.3% and 10 mg/kg memantine by 39.8%. When combined, consumption declined by 48.2% and the proportion of ethanol solution to total fluids consumed declined by 17%. However, the consumption of food also declined by 36.6%. The latter result indicates that this dose combination had a non-specific effect. The combination of SKF 38393 with (+)-MK-801, another NMDA receptor antagonist, also failed to show an additive effect. The lack of additivity and specificity suggests that the hypothesis may not be correct for this in vivo model.  The interaction of these different receptor systems with intraneuronal signaling and behaviors needs to be studied further. Full article
(This article belongs to the Special Issue NMDA Receptor Antagonists for Treatment of CNS Disorders)

Review

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Open AccessReview Current Evidence of Chinese Herbal Constituents with Effects on NMDA Receptor Blockade
Pharmaceuticals 2013, 6(8), 1039-1054; doi:10.3390/ph6081039
Received: 29 May 2013 / Revised: 6 August 2013 / Accepted: 19 August 2013 / Published: 21 August 2013
Cited by 1 | PDF Full-text (138 KB) | HTML Full-text | XML Full-text
Abstract
NMDA receptor (NMDA-R) is an important molecular entity governing a wide range of functions in the central nervous system. For example, the NMDA-R is involved in memory and cognition, and impairment of both (as in Alzheimer’s Disease) is attributed to NMDA-mediated neurotoxicity. [...] Read more.
NMDA receptor (NMDA-R) is an important molecular entity governing a wide range of functions in the central nervous system. For example, the NMDA-R is involved in memory and cognition, and impairment of both (as in Alzheimer’s Disease) is attributed to NMDA-mediated neurotoxicity. With greater understanding of the NMDA-R structure, antagonists with varying degrees of binding-site and subtype selectivity have been developed and put into clinical use. Discovery of target-specific Chinese herbs have also been made in parallel. This article provides an overview of the known active sites on the NMDA-R, followed by a discussion of the relevant herbs and their constituents. Experimental evidence supporting the inhibitory role of the herbal compounds on the NMDA-R is highlighted. For some of the compounds, potential research directions are also proposed to further elucidate the underlying mechanisms of the herbs. It is envisaged that future investigations based on the present data will allow more clinically relevant herbs to be identified. Full article
(This article belongs to the Special Issue NMDA Receptor Antagonists for Treatment of CNS Disorders)
Open AccessReview NMDA Receptor Antagonists for Treatment of Depression
Pharmaceuticals 2013, 6(4), 480-499; doi:10.3390/ph6040480
Received: 31 January 2013 / Revised: 27 March 2013 / Accepted: 27 March 2013 / Published: 3 April 2013
Cited by 5 | PDF Full-text (237 KB) | HTML Full-text | XML Full-text
Abstract
Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. [...] Read more.
Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery. Full article
(This article belongs to the Special Issue NMDA Receptor Antagonists for Treatment of CNS Disorders)
Open AccessReview NMDA Receptor Modulators in the Treatment of Drug Addiction
Pharmaceuticals 2013, 6(2), 251-268; doi:10.3390/ph6020251
Received: 30 November 2012 / Revised: 29 January 2013 / Accepted: 29 January 2013 / Published: 6 February 2013
Cited by 10 | PDF Full-text (304 KB) | HTML Full-text | XML Full-text
Abstract
Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, [...] Read more.
Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function. Full article
(This article belongs to the Special Issue NMDA Receptor Antagonists for Treatment of CNS Disorders)

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