Compound active at a novel site on receptor-operated calcium channels usefull for treatment of neurological disorders and diseases

A compound and composition technology, applied in the field of new active compounds in the treatment of the following diseases

Inactive Publication Date: 2002-08-07
NPS PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Arg-636 potently antagonizes Ca including Glu RAi (Ki=0.35 μM) Glu RCi (Ki=0.23 μM) or Glu RDi subunits (Ki=0.43 μM) 2+ P

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1. Efficient non-competitive inhibition of NMDA receptor function

[0103] In rat cerebellar granule cells cultured in vitro, the effect of arylalkylamine on NMDA receptor-mediated [Ca 2+ ] Preferential inhibitory effect of increased concentrations of i. In the presence or absence of different concentrations of the test compound, NMDA / glycine (50 μM / 1 μM) was added to induce [Ca 2+ ]i concentration increased. Using data from 2-8 independent experiments for each compound tested, the IC was calculated 50 , with a standard error level less than 10% of the mean for each compound.

[0104] All tested arylalkylamine compounds were able to block NMDA / glycine-induced [Ca 2+ ] The increase of i concentration. The inhibitory effect of certain arylalkylamines similar in structure to compounds 1 and 2 was almost as strong as that of MK-801 (IC 50 = 34 nM), the latter being the most potent compound known in the literature to preferentially block NMDA receptors. IC of ...

Embodiment 2

[0105] Example 2. Activity against kainic acid and AMPA receptor function

[0106] In rat cerebellar granule cells [Ca 2+ Determination of the concentration of ]i can also be used to monitor the activation of natural kainic acid and AMPA receptors present in the tissue. Although the [Ca 2+ ]i concentration is not as large as that elicited by NMDA / glycine, but such a response is reliable and can be used to correctly evaluate the effect of arylalkylamines on pharmacologically defined glutamate receptor subtypes specificity of action. [Ca 2+ Comparative measurements of the concentrations of ]i show that the acceptor selectivity of these arylalkylamine compounds is quite pronounced. Certain compounds, such as JSTX-3 (Joro spider toxin extracted from the Nephila clavata spider), were more potent antagonists of responses elicited by kainic acid (100 μM) or AMPA (30 μM). On the other hand, arylalkylamine compounds within the two structural types defined by Compound 1 and Compoun...

Embodiment 3

[0107] Example 3. Electrophysiological study of extracellular patch clamp

[0108] Extracellular patch-clamp electrophysiological studies of cortical or hippocampal neurons isolated from adult rat brains have furthered our understanding of the mechanisms of action of compounds 1, 2, and 3. These studies reveal that arylalkylamine compounds have potent and selective inhibitory effects on NMDA receptor-mediated responses. Thus, compounds like compound 1 can block the response to NMDA at nanomolar concentrations that do not affect the response to kainic acid. These results showing that arylalkylamine compounds are selectively inhibitory in cortical and hippocampal neurons indicate that arylalkylamine compounds target NMDA receptors in different regions of the mammalian CNS. It has also been found that this inhibitory effect of these compounds is use and potential dependent. This strongly suggests that these compounds block open channels and, by doing so, act as non-competitive ...

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PUM

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Abstract

Method for identifying a compound useful for the therapeutic treatment of a neurological disease or disorder such as stroke, head trauma, spinal cord injury, epilepsy, anxiety, or neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease or Parkinson's Disease, or useful as a muscle relaxant, analgesic, or adjuvant to general anesthetics. The compounds is active on a receptor-operated calcium channel, including, but not limited to, that present as part of an NMDA receptor-ionophore complex, a calcium-permeable AMPA receptor, or a nicotinic cholinergic receptor, as a noncompetitive antagonist. The method includes identifying a compound which bonds to the receptor-operated calcium channel at the site bound by the arylalkylamines Compound 1, Compound 2 or Compound 3.

Description

field of invention [0001] The present invention relates to compounds useful as neuroprotective agents, anticonvulsants, anxiolytics, analgesics, muscle relaxants or adjuvants to general anesthetics. The invention also relates to methods useful in the treatment of neurological disorders and other diseases including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, nerve cell damage from hypoxia Examples include cardiac arrest or neonatal distress, epilepsy, anxiety, and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. The present invention also relates to methods for screening compounds that are active at novel sites on receptor-operated calcium channels, so that the compounds of the present invention can be used as neuroprotective agents, anticonvulsants, anxiolytics, analgesics, muscle relaxants agent or adjuvant to general anesthesia, and / or have potential therapeutic...

Claims

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Application Information

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IPC IPC(8): A61K31/405A61K31/135A61K31/136A61K31/137A61K31/138A61K31/14A61K31/165A61K31/17A61K31/295A61K31/381A61K31/40A61K31/403A61K31/404A61K31/4045A61K31/4409A61K31/4462A61K31/4465A61K45/00A61P9/10A61P9/12A61P21/02A61P25/00A61P25/04A61P25/08A61P25/14A61P25/16A61P25/22A61P25/28A61P43/00C07C211/27C07C211/29C07C217/62C07C233/22C07C235/34C07C237/22C07C279/12C07D209/18G01N33/53G01N33/566
CPCG01N2800/28C07C235/34C07D209/18C07C279/14A61K31/138A61K31/136A61K31/165A61K31/381A61K31/4409A61K31/295A61K31/4462A61K31/135C07C237/22A61K31/137A61K31/4465C07C233/22A61K31/404A61K31/40A61P21/02A61P23/00A61P25/00A61P25/04A61P25/08A61P25/14A61P25/16A61P25/22A61P25/28A61P43/00A61P9/10A61P9/12
Inventor A·L·米勒B·C·范韦根伦E·G·德尔马M·F·巴兰德林S·T·莫L·D·阿特曼R·M·巴默尔
Owner NPS PHARM INC
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