Carbon monoxide dependent guanylyl cyclase modifiers and methods of use

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...

AI Technical Summary

Benefits of technology

[0024] As will be appreciated by those skilled in the art, the in vivo activation or derepression of genetic expression and the exemplary modifications of cellular and neural activity brought about by the methods, compositions, and medicaments of the present invention may be expressed in a variety of forms or combinations thereof. For example, the treatment of a mammalian cell or neuron through the teachings of the present invention may result in the cell's direct self-administration of the in vivo expressed molecule(s) through the enhanced cellular production of various naturally occurring genetically encoded compounds, such as proteins and neurotrophic factors, or in the stimulation of the activity of those compounds and their subsequent effect on naturally occurring cellular or neuronal metabolism, function, development, and survival. These subsequent effects can include protection from free radical oxidation and cellular destruction, stabilization of cell receptors against other factors, the endogenous production of carbon monoxide and antioxidant compounds, and even reductions in blood pressure via carbon monoxide activated cellular mechanisms. The methods and medicaments of the present invention may also stimulate the growth, development and survival of the cell or neuron directly without the deleterious effects of prior art factor methodology. Further, the present invention may be used to lower or change the membrane potential of the cell, increasing its plasticity and inducing long term potentiation.

[0026] In a further, more specific aspect, the methods and compositions of the present invention may be used for the treatment or prophylactic prevention of neurological diseases and other cellular disorders, including those brought about by disease, oxidative stress, age, trauma or exposure to harmful chemical agents. By promoting the survival, growth and development of individual neurons and cells, the present invention facilitate the regeneration and development of the neural network and alleviates the manifestations of cellular and neural dysfunction.

[0028] In yet another aspect, the methods and compositions of the present invention may be used to induce long term changes in the membrane potential of a mammalian neuron. These long term potentiation changes may lead to increased membrane plasticity with a corresponding enhancement of cellular memory. In turn, this enhanced cellular memory may elevate the mental capacity of the subject leading to faster learning and increased retention of material.

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 neurotrophic factors to stimulate the regeneration of the neuronal network.

For example, these proteins cannot be delivered to a patient or subject orally as the patient's digestive system would digest them before they reached the target neural site.

Moreover, due to their relatively large size, the proteins cannot cross the blood brain barrier and access the most important neurological site in the body.

Alternatively, the direct injection of neurotrophic factors into the brain or cerebrospinal fluid crudely overcomes this difficulty but is fraught with technical problems of its own which have thus far proven intractable.

For example, direct infusion of known neurotrophins into the brain has proven impractical as it requires administration over a period of years to provide therapeutic concentrations.

Further, direct injection into the brain has been associated with dangerous swelling and inflammation of the nerve tissue after a very short period of time.

Thus, as theoretically desirable as the direct administration of neurotrophic factors to a patient may be, at the present time, it is unfeasible.

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