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All 5 posts Subject: 5,7dichlorokynurenic acid a potent nmda antagonist Please login to post Down

er0x
(Stranger)
10-08-04 04:40
No 534918
      5,7dichlorokynurenic acid a potent nmda antagonist

Searched and could not find much info on 5,7dichlorokynurenic acid. It is one of the most potent nmda antagonists known. It is compared to TCP (potent PCP analog) and dizocilpine +MK801. The only info I could find on dosage was for intra-cerebral-injections which is obviously no good. I need info on oral, IM or SC doses. Also need info on kynurenic acid (dose,fx,etc...)

Nicodem
(Hive Bee)
10-08-04 08:55
No 534937
User Picture       Kynurenic acid and practically all of its...

Kynurenic acid and practically all of its derivatives are inactive. They are not lipophylic enough to pass the blood-brain barrier. Unless you want to administer trough a hole in the brain I suggest you find some other idea. I think there are only very few NMDA complex/glycine receptor antagonists that could potentially pass the BBB. I must have a relevant paper somewhere that will post if I find it.

“The real drug-problem is that we need more and better drugs.” – J. Ott

java
(Hive Addict)
10-08-04 15:57
No 534962
User Picture       Ref. summaries to 5,7,dichlorokynurenic acid......

In searching through the web ,I was able to find these summaries that may be of help.....java

Anticonvulsant activity of 5,7DCKA, NBQX, and felbamate against some chemoconvulsants in DBA/2 mice
Giovambattista De Sarro*, , Ennio Ongini†, Rosalia Bertorelli†, Umberto Aguglia‡ and Angela De Sarro§

Pharmacology Biochemistry and Behavior Volume 55, Issue 2 , October 1996, Pages 281-28
DOI:10.1016/S0091-3057(96)00085-8
Abstract
The anticonvulsant effects of felbamate (10–300 mg/kg, intraperitoneally, IP), and those of two representative antagonists of the excitatory amino acid receptors, 5–7dichlorokynurenic acid (5–7DCKA; 0.6–30 nmol/mouse, intracerebroventricularly, ICV), and 2,3-dihydroxy-6 nitro-7-sulfamoylbenzo(F)quinoxoline (NBQX; 1.1–33.6 mg/kg, IP) were studied in the DBA/2 mice. All drugs protected the animals from sound-induced seizures. The drugs were also effective against seizures induced by stimulation of the excitatory amino acid receptor complex using the agonists N-methyl-D-aspartate (NMDA) or -amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA). In separate studies, felbamate protected mice from seizures induced by ICV administration of the activator of dihydropyridine-sensitive calcium channels, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay k 8644), with ED50 values of 26 and 46.9 mg/kg for tonus and clonus, respectively. Using Bay k 8644, NBQX (1–40 mg/kg IP) was uneffective, while 5,7DCKA (5–90 nmol/mouse, ICV) protected mice against tonus. Moreover, felbamate prevented seizures induced by blocking voltage-dependent K+ channels using -dendrotoxin, with ED50 values of 22.6 mg/kg for tonus and of 34.8 mg/kg for clonus. Conversely, 5,7DCKA or NBQX did not significantly antagonize seizures induced by -dendrotoxin. The present data indicate that felbamate is an effective anticonvulsant drug in DBA/2 mice with a broader anticonvulsant spectrum than 5,7DCKA and NBQX.

Author Keywords: Felbamate; 5,7DCKA (5,7dichlorokynurenic acid); NBQX (2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)quinoxoline); Audiogenic seizures; Voltage-dependent K+ channels; Dihydropyridine-sensitive Ca2+ channels

Competitive NMDA and Strychnine-Insensitive Glycine-Site Antagonists Disrupt Prepulse Inhibition - Is the NMDA-associated glycine receptor saturated in vivo?
Furuya Y.[1]; Ogura H.
Pharmacology Biochemistry and Behavior    August 1997, vol. 57, no. 4,    pp. 909-913(5)
DOI:10.1016/S0091-3057(96)00452-2
Abstract:
Prepulse inhibition (PPI) is thought to reflect the operation of a sensorimotor gating system in the brain. Sensorimotor gating abnormalities have been identified in schizophrenic patients, and various neural systems are involved in this function. To study the modulation of the sensorimotor gating system by the N-methyl-d-aspartate (NMDA) receptor-channel complex, the effects of noncompetitive and competitive NMDA antagonists on PPI were examined in rats. PPI was not disrupted by CGS 19755, a competitive NMDA antagonist, at 30 min after subcutaneous (SC) administration. However, CGS 19755 (40 mg/kg SC) decreased PPI at 120 min after administration with a marked decrease of startle amplitude. Late onset of the effect of CGS 19755 was also observed in the increase of spontaneous locomotor activity (SLA). On the other hand, phencyclidine, a noncompetitive NMDA antagonist, disrupted PPI at 30 min after administration and increased SLA from 20 min after administration. PPI was also disrupted by bilateral intracerebroventricular administration of 5,7-dichlorokynurenate (10 and 20 g/side x 2), an antagonist at the strychnine-insensitive glycine receptor, which is an allosteric binding site in the NMDA receptor-channel complex. It is concluded that the NMDA receptor-channel complex plays an important role in regulation of PPI.

Keywords: Prepulse inhibition; CGS 19755; Phencyclidine; 5,7-Dichlorokyn urenate; NMDA receptor; Strychnine-insensitive glycine receptor; Rat; Spontaneous locomotor activity

It is better to die on your feet than to live on your knees...Emiliano Zapata

er0x
(Stranger)
10-08-04 17:33
No 534970
      damn that sux!

intra-cerebro-ventricular-injections. Sounds like important research.... NOT! How would ICV research benefit anyone who doesn't have a fucking hole in thier head.

Anyway, I read that there is some preliminary research which says attaching a vitamin-C molecule to it may allow it to pass the BBB. How would one go about that/Would it be worth it??? Any thoughtz

Nicodem
(Hive Bee)
10-10-04 11:27
No 535175
User Picture       Glycine-Site NMDA Receptor Antagonists review

This strychnine-insensitive glycine receptor antagonists review is quite pessimistic for those of us who would like to see new dissociatives based on NMDA receptor inhibition mediated through its Gly site. Many antagonists, including kyuneric acid analogues, are described but none of them looks very potent and capable of penetrating trough the BBB at the same time. However for consolation only, this is a review older than ten years and there must have been some progress since.

Glycine-Site N-Methyl-D-Aspartate Receptor Antagonists
Paul D. Leeson
in Drug Design for Neuroscience, edited by Alan P Korikowski, New York: Raven Press (1993)
pp. 339-381

INTRODUCTION
Actions of Glycine in the Central Nervous System
The amino acid glycine has both inhibitory and excitatory actions in the CNS. It has been known for many years that glycine is the major inhibitory neurotransmitter in lower brain regions, acting on strychnine-sensitive receptors in the brainstem and spinal cord. The inhibitory receptor offers limited potential as a target site for therapeutic intervention. but interest in the structurally simplest amino acid was greatly stimulated by the discovery in 1987 of an unexpected excitatory role for glycine in the CNS. Johnson and Ascher (I) demonstrated that glycine profoundly amplifies responses of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor. This novel effect of glycine is not blocked by strychnine and is best explained by the existence of a separate site for glycine on the NMDA receptor. Occupation of this glycine site appears to be an absolute requirement for NMDA receptor activation and has led to the concept that glycine acts as a "coagonist" in concert with the neurotransmitter glutamic acid (2), a unique requirement among neurotransmitter receptors. Mechanisms regulating the physiological role of glycine at NMDA receptors are not as yet fully understood. Although the concentrations of glycine in extracellular and cerebrospinal fluid are above micromolar, evidence from in vivo studies with glycine agonists suggests that the glycine site may not be fully saturated. Currently it seems likely that the phasic release to glutamate from nerve terminals mediates synaptic transmission and that changes in extracellular concentrations of glycine will "modulate" the response mediated by NMDA receptors.

“The real drug-problem is that we need more and better drugs.” – J. Ott

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	All 5 posts		Subject: 5,7dichlorokynurenic acid a potent nmda antagonist		Please login to post		Down


		er0x (Stranger) 10-08-04 04:40 No 534918				5,7dichlorokynurenic acid a potent nmda antagonist
						Searched and could not find much info on 5,7dichlorokynurenic acid. It is one of the most potent nmda antagonists known. It is compared to TCP (potent PCP analog) and dizocilpine +MK801. The only info I could find on dosage was for intra-cerebral-injections which is obviously no good. I need info on oral, IM or SC doses. Also need info on kynurenic acid (dose,fx,etc...)



		Nicodem (Hive Bee) 10-08-04 08:55 No 534937				Kynurenic acid and practically all of its...
						Kynurenic acid and practically all of its derivatives are inactive. They are not lipophylic enough to pass the blood-brain barrier. Unless you want to administer trough a hole in the brain I suggest you find some other idea. I think there are only very few NMDA complex/glycine receptor antagonists that could potentially pass the BBB. I must have a relevant paper somewhere that will post if I find it. “The real drug-problem is that we need more and better drugs.” – J. Ott



		java (Hive Addict) 10-08-04 15:57 No 534962				Ref. summaries to 5,7,dichlorokynurenic acid......
						In searching through the web ,I was able to find these summaries that may be of help.....java Anticonvulsant activity of 5,7DCKA, NBQX, and felbamate against some chemoconvulsants in DBA/2 mice Giovambattista De Sarro, , Ennio Ongini†, Rosalia Bertorelli†, Umberto Aguglia‡ and Angela De Sarro§* Pharmacology Biochemistry and Behavior Volume 55, Issue 2 , October 1996, Pages 281-28 DOI:10.1016/S0091-3057(96)00085-8 Abstract The anticonvulsant effects of felbamate (10–300 mg/kg, intraperitoneally, IP), and those of two representative antagonists of the excitatory amino acid receptors, 5–7dichlorokynurenic acid (5–7DCKA; 0.6–30 nmol/mouse, intracerebroventricularly, ICV), and 2,3-dihydroxy-6 nitro-7-sulfamoylbenzo(F)quinoxoline (NBQX; 1.1–33.6 mg/kg, IP) were studied in the DBA/2 mice. All drugs protected the animals from sound-induced seizures. The drugs were also effective against seizures induced by stimulation of the excitatory amino acid receptor complex using the agonists N-methyl-D-aspartate (NMDA) or -amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA). In separate studies, felbamate protected mice from seizures induced by ICV administration of the activator of dihydropyridine-sensitive calcium channels, methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay k 8644), with ED50 values of 26 and 46.9 mg/kg for tonus and clonus, respectively. Using Bay k 8644, NBQX (1–40 mg/kg IP) was uneffective, while 5,7DCKA (5–90 nmol/mouse, ICV) protected mice against tonus. Moreover, felbamate prevented seizures induced by blocking voltage-dependent K+ channels using -dendrotoxin, with ED50 values of 22.6 mg/kg for tonus and of 34.8 mg/kg for clonus. Conversely, 5,7DCKA or NBQX did not significantly antagonize seizures induced by -dendrotoxin. The present data indicate that felbamate is an effective anticonvulsant drug in DBA/2 mice with a broader anticonvulsant spectrum than 5,7DCKA and NBQX. Author Keywords: Felbamate; 5,7DCKA (5,7dichlorokynurenic acid); NBQX (2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)quinoxoline); Audiogenic seizures; Voltage-dependent K+ channels; Dihydropyridine-sensitive Ca2+ channels Competitive NMDA and Strychnine-Insensitive Glycine-Site Antagonists Disrupt Prepulse Inhibition - Is the NMDA-associated glycine receptor saturated in vivo? Furuya Y.[1]; Ogura H. Pharmacology Biochemistry and Behavior August 1997, vol. 57, no. 4, pp. 909-913(5) DOI:10.1016/S0091-3057(96)00452-2 Abstract: Prepulse inhibition (PPI) is thought to reflect the operation of a sensorimotor gating system in the brain. Sensorimotor gating abnormalities have been identified in schizophrenic patients, and various neural systems are involved in this function. To study the modulation of the sensorimotor gating system by the N-methyl-d-aspartate (NMDA) receptor-channel complex, the effects of noncompetitive and competitive NMDA antagonists on PPI were examined in rats. PPI was not disrupted by CGS 19755, a competitive NMDA antagonist, at 30 min after subcutaneous (SC) administration. However, CGS 19755 (40 mg/kg SC) decreased PPI at 120 min after administration with a marked decrease of startle amplitude. Late onset of the effect of CGS 19755 was also observed in the increase of spontaneous locomotor activity (SLA). On the other hand, phencyclidine, a noncompetitive NMDA antagonist, disrupted PPI at 30 min after administration and increased SLA from 20 min after administration. PPI was also disrupted by bilateral intracerebroventricular administration of 5,7-dichlorokynurenate (10 and 20 g/side x 2), an antagonist at the strychnine-insensitive glycine receptor, which is an allosteric binding site in the NMDA receptor-channel complex. It is concluded that the NMDA receptor-channel complex plays an important role in regulation of PPI. Keywords: Prepulse inhibition; CGS 19755; Phencyclidine; 5,7-Dichlorokyn urenate; NMDA receptor; Strychnine-insensitive glycine receptor; Rat; Spontaneous locomotor activity It is better to die on your feet than to live on your knees...Emiliano Zapata



		er0x (Stranger) 10-08-04 17:33 No 534970				damn that sux!
						intra-cerebro-ventricular-injections. Sounds like important research.... NOT! How would ICV research benefit anyone who doesn't have a fucking hole in thier head. Anyway, I read that there is some preliminary research which says attaching a vitamin-C molecule to it may allow it to pass the BBB. How would one go about that/Would it be worth it??? Any thoughtz



		Nicodem (Hive Bee) 10-10-04 11:27 No 535175				Glycine-Site NMDA Receptor Antagonists review
						This strychnine-insensitive glycine receptor antagonists review is quite pessimistic for those of us who would like to see new dissociatives based on NMDA receptor inhibition mediated through its Gly site. Many antagonists, including kyuneric acid analogues, are described but none of them looks very potent and capable of penetrating trough the BBB at the same time. However for consolation only, this is a review older than ten years and there must have been some progress since. Glycine-Site N-Methyl-D-Aspartate Receptor Antagonists Paul D. Leeson in Drug Design for Neuroscience, edited by Alan P Korikowski, New York: Raven Press (1993) pp. 339-381 INTRODUCTION Actions of Glycine in the Central Nervous System The amino acid glycine has both inhibitory and excitatory actions in the CNS. It has been known for many years that glycine is the major inhibitory neurotransmitter in lower brain regions, acting on strychnine-sensitive receptors in the brainstem and spinal cord. The inhibitory receptor offers limited potential as a target site for therapeutic intervention. but interest in the structurally simplest amino acid was greatly stimulated by the discovery in 1987 of an unexpected excitatory role for glycine in the CNS. Johnson and Ascher (I) demonstrated that glycine profoundly amplifies responses of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor. This novel effect of glycine is not blocked by strychnine and is best explained by the existence of a separate site for glycine on the NMDA receptor. Occupation of this glycine site appears to be an absolute requirement for NMDA receptor activation and has led to the concept that glycine acts as a "coagonist" in concert with the neurotransmitter glutamic acid (2), a unique requirement among neurotransmitter receptors. Mechanisms regulating the physiological role of glycine at NMDA receptors are not as yet fully understood. Although the concentrations of glycine in extracellular and cerebrospinal fluid are above micromolar, evidence from in vivo studies with glycine agonists suggests that the glycine site may not be fully saturated. Currently it seems likely that the phasic release to glutamate from nerve terminals mediates synaptic transmission and that changes in extracellular concentrations of glycine will "modulate" the response mediated by NMDA receptors. “The real drug-problem is that we need more and better drugs.” – J. Ott

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