Review of synthetic approaches to dizocilpine

2020 ◽  
Vol 24 ◽  
Author(s):  
Jan Konecny ◽  
Eva Mezeiova ◽  
Ondrej Soukup ◽  
Jan Korabecny
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Neuronal Plasticity ◽  
Nmda Receptor Antagonist ◽  
Human Medicine ◽  
Ionotropic Glutamate Receptors ◽  
Nmda Receptor Antagonists ◽  
Nmda Antagonists ◽  
The Family ◽  
Synthetic Approaches

Abstract:: N-Methyl-D-aspartate (NMDA) receptors together with AMPA and kainite receptors belongs to the family of ionotropic glutamate receptors. NMDA receptors plays a crucial role in neuronal plasticity and cognitive functions. Overactivation of those receptors leads to glutamate induced excitotoxicity, which could be suppressed by NMDA antagonists. Dizocilpine was firstly reported in 1982 as a NMDA receptor antagonist with anticonvulsive properties, but due to serious side effects like neuronal vacuolization, its use in human medicine is restricted. However, dizocilpine is still used as validated tool to induce the symptoms of schizophrenia in animal models and also as a standart for comparative purposes to newly developed NMDA receptor antagonists. For this reason, synthesis of dizocilpine and specially its more active enantiomer (+)-dizocilpine is still relevant. In this review we bring a collection of various synthetic approaches leading to dizocilpine and its analogues.

scholarly journals Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

2011 ◽  
Vol 301 (2) ◽  
pp. R448-R455 ◽  
Author(s):  
Jason Wright ◽  
Carlos Campos ◽  
Thiebaut Herzog ◽  
Mihai Covasa ◽  
Krzysztof Czaja ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Fourth Ventricle ◽  
Nmda Receptor Antagonist ◽  
Behavioral Pattern ◽  
Vagal Afferents ◽  
Nmda Receptor Antagonists ◽  
The Brain

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

scholarly journals Safety of Cholinesterase Inhibitors and NMDA Receptors Antagonists for the Treatment of Patients with Dementia

2019 ◽  
Vol 7 (4) ◽  
pp. 190-199
Author(s):  
A. P. Pereverzev ◽  
O. D. Ostroumova ◽  
O. N. Tkacheva ◽  
Y. V. Kotovskaya
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Adverse Drug Reactions ◽  
Cholinesterase Inhibitors ◽  
Acetylcholinesterase Inhibitors ◽  
Competitive Inhibitor ◽  
Nmda Receptor Antagonists ◽  
Drug Reactions ◽  
Receptor Antagonists ◽  
Increased Risk

For the treatment of dementia and Alzheimer’s disease, acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or the non-competitive inhibitor of N-methyl-D-aspartate receptors (NMDA receptors) memantine are currently used. The administration of these drugs can help temporarily improve or stabilize memory impairments and other cognitive functions, regress behavioral disorders, reduce the patient’s dependence on others, but at the same time can lead to the development of adverse drug reactions. The aim of this study was to analyze the information on the safety of acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the non-competitive inhibitor of NMDA receptors used to treat dementia. It was shown that stimulation of cholinergic receptors can lead to adverse drug reactions as contraction and narrowing of the pupil (miosis), an increase in lens curvature, accommodation spasm (visual impairment and an increased risk of falls), a decrease in heart rate (bradycardia) and inhibition of conduction of impulses through the conducting system heart, increased tone of the bronchi, gastrointestinal tract, gall and bladder, decreased tone of the sphincters of the digestive tract and bladder, increased secretion of exocrine and glands of the stomach, agitation, confusion. Blockade of NMDA receptors due to impairment of glutamate metabolism in the central nervous system may be the cause of neurotoxicity of NMDA receptor antagonists, and also causes dizziness, feeling of tiredness, hallucinations, drowsiness, and confusion. In case of development of adverse reactions, if possible, it is necessary to stop using the drug or reduce its dose, in case of an overdose or other need, prescribe symptomatic therapy. Information on the safety of cholinesterase inhibitors and NMDA receptor antagonists presented in the article is of practical importance for healthcare professionals, as it allows them to assess the possible risks associated with the use of drugs of these groups more accurately. In addition, the information can be used to optimize and individualize the pharmacotherapy regimens for patients with dementia, including the development of domestic protocols for the deprescribing of drugs (evidence-based practice of withdrawal, replacement or gradual dose reduction) in the elderly. 

NMDA receptor blockade in cat dorsal horn blunts reflex pressor response to muscle contraction and stretch

1996 ◽  
Vol 270 (2) ◽  
pp. H500-H508 ◽  
Author(s):  
G. A. Hand ◽  
A. F. Meintjes ◽  
A. W. Keister ◽  
A. Ally ◽  
L. B. Wilson
Keyword(s):  
Nmda Receptor ◽  
Muscle Contraction ◽  
Nmda Receptors ◽  
Dorsal Horn ◽  
Pressor Response ◽  
Cardiovascular Responses ◽  
Nmda Receptor Antagonist ◽  
Muscle Afferents ◽  
The Central Nervous System ◽  
Passive Stretch

The role of N-methyl-D-aspartate (NMDA) receptors in the reflex pressor response to static muscle contraction and passive stretch was examined by microdialyzing the NMDA receptor antagonist DL-2-amino-5-phosphonovalerate (AP-5) into the L7 or L6 and S1 levels of the dorsal horn of anesthetized cats. Contraction, elicited by electrical stimulation of the cut L7 and S1 ventral roots, increased mean arterial pressure (MAP) and heart rate (HR). Passive stretch at tensions similar to those generated by contraction also increased these variables. These cardiovascular changes were unaffected by dialyzing AP-5 (10 mM) into the dorsal horn at L7. Increasing the syringe concentration of AP-5 to 100 mM attenuated the pressor and HR responses from 62 +/- 8 to 31 +/- 6 mmHg and 18 +/- 4 to 12 +/- 4 beats/min, respectively. AP-5 blunted the increase in MAP (59 +/- 10 vs. 41 +/- 10 mmHg) evoked by muscle stretch. Simultaneously microdialyzing AP-5 (10 or 100 mM) into the dorsal horn at the L6 and S1 spinal levels also blunted the MAP and HR responses to contraction and stretch. These results suggest that NMDA receptors play a role in mediating the MAP and HR responses to static muscle contraction at the spinal level of the central nervous system. Furthermore, these data demonstrate that collaterals from muscle afferents partially mediate the reflex cardiovascular responses evoked by muscle contraction and stretch.

Role of the medullary lateral tegmental field in reflex-mediated sympathoexcitation in cats

2004 ◽  
Vol 286 (3) ◽  
pp. R451-R464 ◽  
Author(s):  
Hakan S. Orer ◽  
Gerard L. Gebber ◽  
Shaun W. Phillips ◽  
Susan M. Barman
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Sympathetic Nerve Activity ◽  
Nmda Receptor Antagonist ◽  
Vagal Afferents ◽  
Reflex Pathways ◽  
Excitatory Responses ◽  
Stimulation Of

We tested the hypothesis that blockade of N-methyl-d-aspartate (NMDA) and non-NMDA receptors on medullary lateral tegmental field (LTF) neurons would reduce the sympathoexcitatory responses elicited by electrical stimulation of vagal, trigeminal, and sciatic afferents, posterior hypothalamus, and midbrain periaqueductal gray as well as by activation of arterial chemoreceptors with intravenous NaCN. Bilateral microinjection of a non-NMDA receptor antagonist into LTF of urethane-anesthetized cats significantly decreased vagal afferent-evoked excitatory responses in inferior cardiac and vertebral nerves to 29 ± 8 and 24 ± 6% of control ( n = 7), respectively. Likewise, blockade of non-NMDA receptors significantly reduced chemoreceptor reflex-induced increases in inferior cardiac (from 210 ± 22 to 129 ± 13% of control; n = 4) and vertebral nerves (from 253 ± 41 to 154 ± 20% of control; n = 7) and mean arterial pressure (from 39 ± 7 to 21 ± 5 mmHg; n = 8). Microinjection of muscimol, but not an NMDA receptor antagonist, caused similar attenuation of these excitatory responses. Sympathoexcitatory responses to the other stimuli were not attenuated by microinjection of a non-NMDA receptor antagonist or muscimol into LTF. In fact, excitatory responses elicited by stimulation of trigeminal, and in some cases sciatic, afferents were enhanced. These data reveal two new roles for the LTF in control of sympathetic nerve activity in cats. One, LTF neurons are involved in mediating sympathoexcitation elicited by activation of vagal afferents and arterial chemoreceptors, primarily via activation of non-NMDA receptors. Two, non-NMDA receptor-mediated activation of other LTF neurons tonically suppresses transmission in trigeminal-sympathetic and sciatic-sympathetic reflex pathways.

Interaction of Dopamine D1 and NMDA Receptors Mediates Acute Clozapine Potentiation of Glutamate EPSPs in Rat Prefrontal Cortex

2002 ◽  
Vol 87 (5) ◽  
pp. 2324-2336 ◽  
Author(s):  
Long Chen ◽  
Charles R. Yang
Keyword(s):  
Prefrontal Cortex ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Ampa Receptors ◽  
Nmda Receptor Antagonist ◽  
D1 Receptor ◽  
Resting Membrane Potential ◽  
Cellular Mechanisms ◽  
Cognitive Improvement

The atypical antipsychotic drug clozapine effectively alleviates both negative and positive symptoms of schizophrenia via unclear cellular mechanisms. Clozapine may modulate both glutamatergic and dopaminergic transmission in the prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole cell patch-clamp techniques, current-clamp recordings in layers V–VI pyramidal neurons from rat PFC slices showed that stimulation of local afferents (in 2 μM bicuculline) evoked mixed [AMPA/kainate and N-methyl-d-aspartate (NMDA) receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs). Clozapine (1 μM) potentiated polysynaptically mediated evoked EPSPs ( V Hold = −65 mV), or reversed EPSPs (rEPSP, V Hold = +20 mV) for >30 min. The potentiated EPSPs or rEPSPs were attenuated by elevating [Ca2+]O(7 mM), by application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50 μM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1 μM) but could be further enhanced by a dopamine reuptake inhibitor bupropion (1 μM). Clozapine had no significant effect on pharmacologically isolated evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without changing the steady-state resting membrane potential. Under voltage clamp, clozapine (1 μM) enhanced the frequency, and the number of low-amplitude (5–10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such changes with the mini-EPSCs (in 1 μM TTX). Taken together these data suggest that acute clozapine can increase spike-dependent presynaptic release of glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors to increase spontaneous EPSCs and enabled a voltage-dependent activation of neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1 receptor to modulate a lasting potentiation of the NMDA receptor component of the glutamatergic synaptic responses in the PFC neuronal network. This sequence of early synaptic events induced by acute clozapine may comprise part of the activity that leads to later cognitive improvement in schizophrenia.

Nicotine-induced anxiogenic-like behaviours of rats in the elevated plus-maze: possible role of NMDA receptors of the central amygdala

2011 ◽  
Vol 26 (4) ◽  
pp. 555-563 ◽  
Author(s):  
Mohammad Reza Zarrindast ◽  
Arash Aghamohammadi-Sereshki ◽  
Ameneh Rezayof ◽  
Parvin Rostami
Keyword(s):  
Locomotor Activity ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Elevated Plus Maze ◽  
Nmda Receptor Antagonist ◽  
Central Amygdala ◽  
Receptor System ◽  
Plus Maze ◽  
Male Wistar Rats

The objective of the present study was to investigate the possible role of the N-methyl-D-aspartate (NMDA) receptor system of the central amygdala (CeA) in the anxiogenic-like effect of nicotine. Male Wistar rats with cannulas aimed to the CeA were submitted to the elevated plus-maze (EPM). Intraperitoneal (i.p.) injections of nicotine (0.6 and 0.8 mg/kg) decreased percentage open arm time spent (%OAT) and percentage open arm entries (%OAE), but not locomotor activity, indicating an anxiogenic-like response. Bilateral intra-CeA microinjection of NMDA (0.005–0.1 μ g/rat) decreased %OAT, but not %OAE and locomotor activity. Moreover, intra-CeA microinjection of NMDA (0.05 μ g) with an ineffective dose of nicotine (0.4 mg/kg, i.p.) reduced %OAT and %OAE without effect on locomotor activity. On the other hand, intra-CeA microinjection of the NMDA receptor antagonist D-AP5 (0.05–0.5 μ g/rat) increased both %OAT and %OAE, showing an anxiolytic-like effect of the drug. Co-administration of the same doses of D-AP5 with nicotine (0.6 mg/kg, i.p.) increased %OAT and %OAE, but not locomotor activity. Intra-CeA microinjection of D-AP5 reversed the response induced by NMDA (0.1 μ g/rat) in the EPM. The results may support the possible involvement of glutamate transmission, through NMDA receptors of central amygdala in the anxiogenic-like effect of nicotine in the EPM task.

scholarly journals Ionotropic Glutamate Receptors in Hypothalamic Paraventricular and Supraoptic Nuclei Mediate Vasopressin and Oxytocin Release in Unanesthetized Rats

Endocrinology ◽  
2012 ◽  
Vol 153 (5) ◽  
pp. 2323-2331 ◽  
Author(s):  
Cristiane Busnardo ◽  
Carlos C. Crestani ◽  
Leonardo B. M. Resstel ◽  
Rodrigo F. Tavares ◽  
José Antunes-Rodrigues ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Glutamate Receptors ◽  
Plasma Levels ◽  
Receptor Agonist ◽  
Local Treatment ◽  
Nmda Receptor Antagonist ◽  
Oxytocin Release ◽  
Circulating Levels

We report changes in plasma arginine vasopressin (AVP) and oxytocin (OT) concentrations evoked by the microinjection of l-glutamate (l-glu) into the hypothalamic supraoptic nucleus (SON) and paraventricular nucleus (PVN) of unanesthetized rats, as well as which local mechanisms are involved in their mediation. l-Glu microinjection (10 nmol/100 nl) into the SON increased the circulating levels of both AVP and OT. The AVP increases were blocked by local pretreatment with the selective non-N-methyl-d-aspartate (NMDA) receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) (2 nmol/100 nl), but it was not affected by pretreatment with the NMDA-receptor antagonist LY235959 (2 nmol/100 nl). The OT response to l-glu microinjection into the SON was blocked by local pretreatment with either NBQX or LY235959. Furthermore, the administration of either the non-NMDA receptor agonist (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) (5 nmol/100 nl) or NMDA receptor agonist NMDA (5 nmol/100 nl) into the SON had no effect on OT baseline plasma levels, but when both agonists were microinjected together these levels were increased. l-Glu microinjection into the PVN did not change circulating levels of either AVP or OT. However, after local pretreatment with LY235959, the l-glu microinjection increased plasma levels of the hormones. The l-glu microinjection into the PVN after the local treatment with NBQX did not affect the circulating AVP and OT levels. Therefore, results suggest the AVP release from the SON is mediated by activation of non-NMDA glutamate receptors, whereas the OT release from this nucleus is mediated by an interaction of NMDA and non-NMDA receptors. The present study also suggests an inhibitory role for NMDA receptors in the PVN on the release of AVP and OT.

scholarly journals Hindbrain administration of NMDA receptor antagonist AP-5 increases food intake in the rat

2006 ◽  
Vol 290 (3) ◽  
pp. R642-R651 ◽  
Author(s):  
Chun-Yi Hung ◽  
M. Covasa ◽  
R. C. Ritter ◽  
G. A. Burns
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Intraperitoneal Injection ◽  
Sucrose Solution ◽  
Nmda Receptor Antagonist ◽  
Saline Control ◽  
Sucrose Intake ◽  
Mk 801

Hindbrain administration of MK-801, a noncompetitive N-methyl-d-aspartate (NMDA) channel blocker, increases meal size, suggesting NMDA receptors in this location participate in control of food intake. However, dizocilpine (MK-801) reportedly antagonizes some non-NMDA ion channels. Therefore, to further assess hindbrain NMDA receptor participation in food intake control, we measured deprivation-induced intakes of 15% sucrose solution or rat chow after intraperitoneal injection of either saline vehicle or d(-)-2-amino-5-phosphonopentanoic acid (AP5), a competitive NMDA receptor antagonist, to the fourth ventricular, or nucleus of the solitary tract (NTS). Intraperitoneal injection of AP5 (0.05, 0.1, 1.0, 3.0, and 5.0 mg/kg) did not alter 30-min sucrose intake at any dose (10.7 ± 0.4 ml, saline control) (11.0 ± 0.8, 11.2 ± 1.0, 11.2 ± 1.0, 13.1 ± 2.2, and 11.0 ± 1.9 ml, AP5 doses, respectively). Fourth ventricular administration of both 0.2 μg (16.7 ± 0.6 ml) and 0.4 μg (14.9 ± 0.5 ml) but not 0.1 and 0.6 μg of AP5 significantly increased 60-min sucrose intake compared with saline (11.2 ± 0.4 ml). Twenty-four hour chow intake also was increased compared with saline (AP5: 31.5 ± 0.1 g vs. saline: 27.1 ± 0.6 g). Furthermore, rats did not increase intake of 0.2% saccharin after fourth ventricular AP5 administration (AP5: 9.8 ± 0.7ml, vs. saline: 10.5 ± 0.5ml). Finally, NTS AP5 (20 ng/30 nl) significantly increased 30- (AP5: 17.2 ± 0.7 ml vs. saline: 14.6 ± 1.7 ml), and 60-min (AP5: 19.4 ± 0.6 ml vs. saline: 15.5 ± 1.4 ml) sucrose intake, as well as 24-h chow intake (AP5: 31.6 ± 0.3 g vs. saline: 26.1 ± 1.2 g). These results support the hypothesis that hindbrain NMDA receptors participate in control of food intake and suggest that this participation also may contribute to control of body weight over a 24-h period.

scholarly journals CCK-Induced Reduction of Food Intake and Hindbrain MAPK Signaling Are Mediated by NMDA Receptor Activation

Endocrinology ◽  
2012 ◽  
Vol 153 (6) ◽  
pp. 2633-2646 ◽  
Author(s):  
Carlos A. Campos ◽  
Jason S. Wright ◽  
Krzysztof Czaja ◽  
Robert C. Ritter
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Fourth Ventricle ◽  
Receptor Activation ◽  
Nmda Receptor Antagonist ◽  
Vagal Afferents ◽  
Mapk Kinase ◽  
Vagal Afferent

The dorsal vagal complex of the hindbrain, including the nucleus of the solitary tract (NTS), receives neural and humoral afferents that contribute to the process of satiation. The gut peptide, cholecystokinin (CCK), promotes satiation by activating gastrointestinal vagal afferents that synapse in the NTS. Previously, we demonstrated that hindbrain administration of N-methyl-d-aspartate (NMDA)-type glutamate receptor antagonists attenuate reduction of food intake after ip CCK-8 injection, indicating that these receptors play a necessary role in control of food intake by CCK. However, the signaling pathways through which hindbrain NMDA receptors contribute to CCK-induced reduction of food intake have not been investigated. Here we report CCK increases phospho-ERK1/2 in NTS neurons and in identified vagal afferent endings in the NTS. CCK-evoked phospho-ERK1/2 in the NTS was attenuated in rats pretreated with capsaicin and was abolished by systemic injection of a CCK1 receptor antagonist, indicating that phosphorylation of ERK1/2 occurs in and is mediated by gastrointestinal vagal afferents. Fourth ventricle injection of a competitive NMDA receptor antagonist, prevented CCK-induced phosphorylation of ERK1/2 in hindbrain neurons and in vagal afferent endings, as did direct inhibition of MAPK kinase. Finally, fourth ventricle administration of either a MAPK kinase inhibitor or NMDA receptor antagonist prevented the reduction of food intake by CCK. We conclude that activation of NMDA receptors in the hindbrain is necessary for CCK-induced ERK1/2 phosphorylation in the NTS and consequent reduction of food intake.

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