NMDA Receptor Structure
Published by Anonymous on 2007/9/30 (2948 reads)
1: Curr Top Med Chem. 2006;6(7):723-32.
Relationships between the structure of dexoxadrol and etoxadrol analogues and their NMDA receptor affinity.
Sax M, Wünsch B.
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Germany.
In the mid 1960s the (dioxolan-4-yl)piperidine derivatives dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a) were synthesized. Their pharmacological potential as analgesics, anesthetics and local anesthetics was evaluated in animal models and later on in clinical trials with patients. However, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol and etoxadrol. Both dioxolane derivatives represent NMDA receptor antagonists, which possess high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel. In this review relationships between the structure of acetalic dexoxadrol analogues and homologues and their affinity toward the phencyclidine binding site of the NMDA receptor are summarized. In particular, high affinity is attained with compounds bearing two phenyl residues or one phenyl residue and an alkyl residue with two or three carbon atoms at the acetalic center. At least one oxygen atom of the oxygen heterocycle is necessary. Instead of the entire piperidine ring aminoalkyl substructures are sufficient for strong receptor interactions. Compounds with a primary amino moiety generally display the highest receptor affinity, whereas tertiary amines possess low affinity. Enlargement of the 1,3-dioxolane ring to a 1,3-dioxane ring or elongation of the oxygen heterocycle / amino group distance results in compounds with considerable NMDA receptor affinity.
Publication Types:
Review
PMID: 16719812 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Curr Top Med Chem. 2006;6(7):663-86.
NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling.
Schrattenholz A, Soskic V.
ProteoSys AG, Mainz, Germany. andre.schrattenholz@proteosys.com
Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.
Publication Types:
Review
PMID: 16719808 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Curr Drug Targets. 2001 Sep;2(3):313-22.
Structure-function relationships of the NMDA receptor antagonist conantokin peptides.
Prorok M, Castellino FJ.
Department of Chemistry and Biochemistry, and the W.M.Keck Center for Transgene Research, University of Notre Dame, Indiana 46556, USA.
The three members of the conantokin peptide family identified to date are conantokin(con)-G, -T and -R. Their defining attributes include a high relative content of gamma-carboxyglutamic acid (Gla), N-terminal sequence identity, as well as considerable overall sequence homology, and antagonism of the N-methyl-D-aspartate receptor (NMDAR). As promising templates for the design of neuroprotective agents, a thorough evaluation of structure-function relationships in these peptides will be invaluable in aiding rational drug modeling. To this end, a comprehensive assessment of the contributions of individual residues to conantokin structure and function is required. The current review summarizes recent efforts in this area, and also includes the effects of peptide length, as well as structural-stabilization and -destabilization on the structural and inhibitory profiles of an extensive panel ofconantokin derivatives.
Publication Types:
Review
PMID: 11554555 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Pharm Unserer Zeit. 2000 Jul;29(4):228-36.
[Structure, function and potential therapeutic possibilities of NMDA receptors. 2. Therapy concepts and new receptor ligands]
[Article in German]
Stark H, Reichert U, Grassmann S.
Freie Universität Berlin, Institut für Pharmazie, Germany. stark@schunet.pharmazie.fu-berlin.de
Publication Types:
Review
PMID: 10969535 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Curr Med Chem. 1998 Aug;5(4):253-63.
The glycine site on the NMDA receptor: structure-activity relationships and possible therapeutic applications.
Dannhardt G, Kohl BK.
Institute of Pharmacy, Johannes Gutenberg-University, Staudingerweg 5, Mainz, D-55099, Germany.
L-glutamate is the most important fast excitatory neurotransmitter in the mammalian central nervous system. Glutamate receptors are classified into two main categories: ionotropic and metabotropic. The N-methyl-D-aspartate (NMDA) receptor, which is associated with an ion channel, seems to play an important role in glutamate excitotoxicity, a process thought to be involved in a number of neurodegenerative disorders such as focal cerebral ischaemia (stroke), Parkinsonís, Huntingtonís, Alzheimerís disease, schizophrenia and epilepsy. The unique glycine site on the NMDA receptor, discovered by Johnson and Ascher in 1987, represents an interesting target for the development of neuroprotective compounds. Glycine antagonists may offer advantages over other NMDA antagonists in terms of their side-effect profile, especially in the long-term treatment of chronical neurodegenerative disorders but also in the treatment of serious medical emergencies with a significant morbidity and mortality like status epilepticus or stroke. So far it is not clear whether NMDA receptor antagonists including glycine antagonists would be suitable for chronic administration because of their effects on cognition, learning and motor function. High-affinity, in vivo potent, glycine antagonists of great structural diversity (i. e. pyrido[2,3-b]pyrazine-N-oxides, indole-2-carboxylates, 4-substituted-3-phenylquinoline-2(1H)-ones and alkyl-substituted 1,4-dihydro-quinoxaline-2,3-diones) are now available and their suitability for long-term treatment of chronical neurodegenerative disorders has to be investigated in clinical trials.
Publication Types:
Review
PMID: 9668194 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Neuropharmacology. 1995 Oct;34(10):1219-37.
Structure and function of the NMDA receptor channel.
Mori H, Mishina M.
Department of Pharmacology, Faculty of Medicine, University of Tokyo, Japan.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8570021 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: J Med Chem. 1994 Nov 25;37(24):4053-67.
The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential.
Leeson PD, Iversen LL.
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
Publication Types:
Review
PMID: 7990104 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Adv Exp Med Biol. 1991;287:483-7.
NMDA receptor agonists: relationships between structure and biological activity.
Ebert B, Madsen U, Johansen TN, Krogsgaard-Larsen P.
Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1836933 [PubMed - indexed for MEDLINE]
Relationships between the structure of dexoxadrol and etoxadrol analogues and their NMDA receptor affinity.
Sax M, Wünsch B.
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Germany.
In the mid 1960s the (dioxolan-4-yl)piperidine derivatives dexoxadrol ((S,S)-1a) and etoxadrol ((S,S,S)-2a) were synthesized. Their pharmacological potential as analgesics, anesthetics and local anesthetics was evaluated in animal models and later on in clinical trials with patients. However, severe side effects including psychotomimetic effects, unpleasant dreams and aberrations stopped the clinical evaluation of dexoxadrol and etoxadrol. Both dioxolane derivatives represent NMDA receptor antagonists, which possess high affinity to the phencyclidine binding site within the NMDA receptor associated ion channel. In this review relationships between the structure of acetalic dexoxadrol analogues and homologues and their affinity toward the phencyclidine binding site of the NMDA receptor are summarized. In particular, high affinity is attained with compounds bearing two phenyl residues or one phenyl residue and an alkyl residue with two or three carbon atoms at the acetalic center. At least one oxygen atom of the oxygen heterocycle is necessary. Instead of the entire piperidine ring aminoalkyl substructures are sufficient for strong receptor interactions. Compounds with a primary amino moiety generally display the highest receptor affinity, whereas tertiary amines possess low affinity. Enlargement of the 1,3-dioxolane ring to a 1,3-dioxane ring or elongation of the oxygen heterocycle / amino group distance results in compounds with considerable NMDA receptor affinity.
Publication Types:
Review
PMID: 16719812 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Curr Top Med Chem. 2006;6(7):663-86.
NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling.
Schrattenholz A, Soskic V.
ProteoSys AG, Mainz, Germany. andre.schrattenholz@proteosys.com
Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.
Publication Types:
Review
PMID: 16719808 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Curr Drug Targets. 2001 Sep;2(3):313-22.
Structure-function relationships of the NMDA receptor antagonist conantokin peptides.
Prorok M, Castellino FJ.
Department of Chemistry and Biochemistry, and the W.M.Keck Center for Transgene Research, University of Notre Dame, Indiana 46556, USA.
The three members of the conantokin peptide family identified to date are conantokin(con)-G, -T and -R. Their defining attributes include a high relative content of gamma-carboxyglutamic acid (Gla), N-terminal sequence identity, as well as considerable overall sequence homology, and antagonism of the N-methyl-D-aspartate receptor (NMDAR). As promising templates for the design of neuroprotective agents, a thorough evaluation of structure-function relationships in these peptides will be invaluable in aiding rational drug modeling. To this end, a comprehensive assessment of the contributions of individual residues to conantokin structure and function is required. The current review summarizes recent efforts in this area, and also includes the effects of peptide length, as well as structural-stabilization and -destabilization on the structural and inhibitory profiles of an extensive panel ofconantokin derivatives.
Publication Types:
Review
PMID: 11554555 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Pharm Unserer Zeit. 2000 Jul;29(4):228-36.
[Structure, function and potential therapeutic possibilities of NMDA receptors. 2. Therapy concepts and new receptor ligands]
[Article in German]
Stark H, Reichert U, Grassmann S.
Freie Universität Berlin, Institut für Pharmazie, Germany. stark@schunet.pharmazie.fu-berlin.de
Publication Types:
Review
PMID: 10969535 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Curr Med Chem. 1998 Aug;5(4):253-63.
The glycine site on the NMDA receptor: structure-activity relationships and possible therapeutic applications.
Dannhardt G, Kohl BK.
Institute of Pharmacy, Johannes Gutenberg-University, Staudingerweg 5, Mainz, D-55099, Germany.
L-glutamate is the most important fast excitatory neurotransmitter in the mammalian central nervous system. Glutamate receptors are classified into two main categories: ionotropic and metabotropic. The N-methyl-D-aspartate (NMDA) receptor, which is associated with an ion channel, seems to play an important role in glutamate excitotoxicity, a process thought to be involved in a number of neurodegenerative disorders such as focal cerebral ischaemia (stroke), Parkinsonís, Huntingtonís, Alzheimerís disease, schizophrenia and epilepsy. The unique glycine site on the NMDA receptor, discovered by Johnson and Ascher in 1987, represents an interesting target for the development of neuroprotective compounds. Glycine antagonists may offer advantages over other NMDA antagonists in terms of their side-effect profile, especially in the long-term treatment of chronical neurodegenerative disorders but also in the treatment of serious medical emergencies with a significant morbidity and mortality like status epilepticus or stroke. So far it is not clear whether NMDA receptor antagonists including glycine antagonists would be suitable for chronic administration because of their effects on cognition, learning and motor function. High-affinity, in vivo potent, glycine antagonists of great structural diversity (i. e. pyrido[2,3-b]pyrazine-N-oxides, indole-2-carboxylates, 4-substituted-3-phenylquinoline-2(1H)-ones and alkyl-substituted 1,4-dihydro-quinoxaline-2,3-diones) are now available and their suitability for long-term treatment of chronical neurodegenerative disorders has to be investigated in clinical trials.
Publication Types:
Review
PMID: 9668194 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Neuropharmacology. 1995 Oct;34(10):1219-37.
Structure and function of the NMDA receptor channel.
Mori H, Mishina M.
Department of Pharmacology, Faculty of Medicine, University of Tokyo, Japan.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 8570021 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
7: J Med Chem. 1994 Nov 25;37(24):4053-67.
The glycine site on the NMDA receptor: structure-activity relationships and therapeutic potential.
Leeson PD, Iversen LL.
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
Publication Types:
Review
PMID: 7990104 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
8: Adv Exp Med Biol. 1991;287:483-7.
NMDA receptor agonists: relationships between structure and biological activity.
Ebert B, Madsen U, Johansen TN, Krogsgaard-Larsen P.
Department of Organic Chemistry, Royal Danish School of Pharmacy, Copenhagen.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 1836933 [PubMed - indexed for MEDLINE]
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