Carbon monoxide dependent guanylyl cyclase modifiers and methods of use

a guanylyl cyclase and carbon monoxide technology, applied in the direction of biocide, immunological disorders, drug compositions, etc., can solve the problems of inability to effectively compensate for loss, reduced acetylcholine binding sites, etc., to achieve the effect of increasing acetylcholine binding sites

Inactive Publication Date: 2006-03-23
SPECTRUM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0076] The interaction of AIT-082 with acetylcholine receptors was determined by interference with the binding of QNB (3-quinuclidinyl benzilate) in mouse tissue using the method of Fields [J. Biol. Chem. 253(9): 3251-3258, 1978]. There was no effect of AIT-082 in this assay.
[0077] In the study, mice were treated with AIT-082 at 30 mg/kg 2 hours prior to sacrifice, decapitated and the tissue processed to obtain membranes containing the acetylcholine receptors. When these tissues were assayed in vitro, there was no effect of AIT-082 on affinity (Kd) for QNB when AIT-082 was administered under the same conditions as utilized in testing for effects on memory. There was a change in the number of receptors (B max) in cortex and striatum, wit...

Problems solved by technology

Unfortunately, when the biochemical matrix of the central nervous system is damaged, either through age, disease or other reasons, the normal regulatory pathways may be incapable of effectively compensating for the loss.
Conversely, when the connections within the neural network break down as nerve cells die or degenerate due to age, disease, oxidative stress, or direct physical insult, the mental capacity of the organism can be severely compromised.
Similar problems may be brought about by loss of neuronal connectivity due to normal aging or through damage to neurons from stroke, heart attack, or other circulatory complications.
Direct physical trauma or environmental factors including chemical agents, heavy metals and the like may also provoke neuronal or cellular distress, dysfunction, or death.
Neurons are deficient in this antioxidant source.
At present, prior art techniques and compounds have not been effective or practical to directly administer neurotrophic factors to a patient suffering from a neural disorder.
Other practical considerations also preclude the prior art use of neu...

Method used

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  • Carbon monoxide dependent guanylyl cyclase modifiers and methods of use
  • Carbon monoxide dependent guanylyl cyclase modifiers and methods of use
  • Carbon monoxide dependent guanylyl cyclase modifiers and methods of use

Examples

Experimental program
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Effect test

example 1

Plasma Levels of AIT-082 in Mice

[0069] Adult C57BL / 6 mice were administered 30 mg / kg of AIT-082 in saline i.p. The animals were sacrificed by decapitation at 30, 45, 60 and 90 minutes after administration of AIT-082. Blood was collected in heparinized tubes, mixed and centrifuged at 2000 rpm for 15 minutes. The plasma supernatant was removed and stored at −70° C. until analysis. A high pressure liquid chromatography system was developed for the analytical measurement of AIT-082 in plasma and brain tissue. The assay developed was selective for AIT-082 in the presence of a number of closely related purine molecules. The sensitivity of the method was 0.1 microgram of AIT-082 per ml of plasma and 0.1 microgram of AIT-082 per milligram of brain tissue (wet weight).

[0070] The results of these determinations are shown in Table A and graphically represented in FIG. 1 where plasma levels of AIT-082 are provided at 30, 45 and 60 minutes after administration of 30 mg / kg i.p. to C57BL / 6 mice....

example 2

AIT-082 Crosses the Blood Brain Barrier

[0071] Brain tissue was analyzed from two animals receiving 30 mg / kg i.p. of AIT-082 and sacrificed 30 minutes after drug administration. The brains were rapidly removed and chilled on ice. Brain tissue was dissected into cortex and remainder of the brain. Brain tissue (approx. 250-300 mg wet weight) was homogenized with 5.0 ml of saline using a Brinkman Polytron tissue grinder and stored at −70° C. until analysis. Brain homogenates were deproteinized by ultrafiltration through Gelman Acrodisc filters; first through a 1.2 micron filter and then through a 0.2 micron filter. A 30 μl sample was injected into the HPLC for analysis as above. A standard curve was prepared by the addition of known quantities of AIT-082 to brain homogenates from untreated animals. Analysis of the brain tissue indicated that AIT-082 was detected in both the cortex sample and the remaining brain samples from both animals. The results are shown directly below in Table B....

example 3

AIT-082 Interacts with the Cholinergic System

[0073] Because of the finding that there is a severe loss of cholinergic neurons in the hippocampus in Alzheimer's disease patients, there has been considerable interest in the effect on memory of compounds which alter the activity of this system. Support for the cholinergic hypothesis of memory comes from studies using lesions or a stroke model. Lesions of the CA1 region of the hippocampus appear to specifically disrupt working memory. In the stroke model, occlusion of the vertebral and carotid arteries (30 minutes) produces specific cell loss in the CA1 region of the hippocampus and a loss of working memory. In these models in aged rats, physostigmine, a cholinesterase inhibitor, has been shown to improve memory. THA, another drug which increases cholinergic function, was shown to improve memory in aged monkeys. The observation that AIT-082 improves memory in the same general manner as physostigmine and THA raises the question of wheth...

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Abstract

Disclosed herein are methods and associated compositions and medicaments directed generally to the control of cellular and neural activity and for selectively and controllably inducing the in vivo genetic expression of one or more naturally occurring genetically encoded molecules in mammals. More particularly, the present invention selectively activates or derepresses genes encoding for specific naturally occurring molecules such as proteins or neurotrophic factors and induces the endogenous production of such naturally occurring compounds through the administration of carbon monoxide dependent guanylyl cyclase modulating purine derivatives. The methods of the present invention may be used to affect a variety of cellular and neurological functions and activities and to therapeutically or prophylactically treat a wide variety of neurodegenerative, neurological, cellular, and physiological disorders.

Description

RELATED APPLICATIONS [0001] The present invention is a continuation-in-part of co-pending application Ser. No. 08 / 488,976, filed Jun. 8, 1995, which is a continuation-in-part of co-pending application Ser. No. 08 / 280,719, filed Jul. 25, 1994.FIELD OF THE INVENTION [0002] The present invention relates in general to the control of cellular and neural activity and to the treatment of cellular and neural disorders. More particularly, the present invention is directed to methods and associated compositions and medicaments for the modification of mammalian cellular and neural activity through the administration of carbon monoxide dependent guanylyl cyclase modulating purine derivatives which selectively and controllably induce the in vivo genetic expression of naturally occurring genetically encoded molecules including neurotrophic factors. The methods, compositions, and medicaments of the present invention may be used to affect a variety of cellular and neurological activities and to the...

Claims

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Application Information

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IPC IPC(8): A61K31/522A61K31/52C07D473/30A61K31/70A61P25/00A61P25/28A61P37/00
CPCA61K31/52A61K31/708A61K31/7076A61K31/522A61P25/00A61P25/28A61P37/00
Inventor GLASKY, ALVIN J.RATHBONE, MICHEL P.
Owner SPECTRUM PHARMA INC
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