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.

1 . A method for the treatment of mammalian disease conditions associated with cellular damage due to oxidative stress, said method comprising the step of inducing the in vivo production of at least one naturally occurring endogenous antioxidant by treating a mammalian subject with an effective amount of at least one carbon monoxide dependent guanylyl cyclase modulating purine derivative.  
   
   
       2 . The method of  claim 1  wherein said carbon monoxide dependent guanylyl cyclase modulating purine derivative is selected from the group consisting of guanosine, 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxo-propyl]amino]benzoic acid, and inosine pranobex.  
   
   
       3 . The method of  claim 1  wherein said effective amount of said at least one carbon monoxide dependent guanylyl cyclase modulating purine derivative produces a treating concentration of at least 1 μM.  
   
   
       4 . The method of  claim 2  wherein said mammalian subject is treated by orally administering said at least one carbon monoxide dependent guanylyl cyclase modulating purine derivative.  
   
   
       5 . The method of  claim 2  wherein said mammalian subject is treated by injecting said at least one carbon monoxide dependent guanylyl cyclase modulating purine derivative.  
   
   
       6 . The method of  claim 1  wherein said mammalian disease condition is Alzheimer's disease and related degenerative disorders.  
   
   
       7 . The method of  claim 1  wherein said mammalian disease condition is old age benign forgetfulness and related disorders.  
   
   
       8 . The method of  claim 1  wherein said mammalian disease condition is aging related loss of neurons or neuronal connectivity and related deterioration of sensory, motor, reflex, or cognitive abilities.  
   
   
       9 . The method of  claim 1  wherein said mammalian disease condition is Parkinson's disease and related disorders.  
   
   
       10 . The method of  claim 1  wherein said mammalian disease condition is spino-cerebellar atrophy.  
   
   
       11 . The method of  claim 1  wherein said mammalian disease condition is motor neuronopathy or Amyotrophic Lateral Sclerosis.  
   
   
       12 . The method of  claim 1  wherein said mammalian disease condition is damage to neurons or their processes by physical agents.  
   
   
       13 . The method of  claim 1  wherein said mammalian disease condition is damage to neurons by ischemia, anoxia, hypoxia, or hypoglycemia.  
   
   
       14 . The method of  claim 1  wherein said mammalian disease condition is damage to neurons by chemical agents.  
   
   
       15 . The method of  claim 1  wherein said mammalian disease condition is trauma to the heart, brain or spinal cord.  
   
   
       16 . The method of  claim 1  wherein said mammalian disease condition is epilepsy or seizures.  
   
   
       17 . The method of  claim 1  wherein said mammalian disease condition is peripheral neuropathy.  
   
   
       18 . The method of  claim 1  wherein said mammalian disease condition is learning disability.  
   
   
       19 . The method of  claim 1  wherein said mammalian disease condition is cerebral palsy.  
   
   
       20 . The method of  claim 1  wherein said mammalian disease condition is psychiatric disorder.  
   
   
       21 . The method of  claim 1  wherein said mammalian disease condition is memory disorder.  
   
   
       22 . The method of  claim 1  wherein said mammalian disease condition is Huntington's disease.  
   
   
       23 . The method of  claim 1  wherein said endogenous antioxidant is a bile pigment.  
   
   
       24 . The method of  claim 23  wherein said bile pigment is selected from the group consisting of biliverdin or bilirubin.  
   
   
       25 . The method of  claim 23  wherein said bile pigment is produced through the Additional step of degrading heme with heme oxygenase.  
   
   
       26 . A method for inducing the in vivo production of heme oxygenase in a mammal, said method comprising the step of treating a mammal with an effective amount of at least one carbon monoxide dependent guanylyl cyclase modulating purine derivative.  
   
   
       27 . The method of  claim 26  wherein said carbon monoxide dependent guanylyl cyclase modulating purine derivative is selected from the group consisting of guanosine, 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxo-propyl]amino]benzoic acid, and inosine pranobex.  
   
   
       28 . The method of  claim 26  wherein said effective amount of said at least one carbon monoxide dependent guanylyl cyclase modulating purine derivative produces a treating concentration of at least 1 μM.  
   
   
       29 . The method of  claim 27  wherein said mammal is treated by orally administering said at least one carbon monoxide dependent guanylyl cyclase modulating purine derivative.  
   
   
       30 . The method of  claim 27  wherein said mammal is treated by injecting said at least one carbon monoxide dependent guanylyl cyclase modulating purine derivative.  
   
   
       31 . The method of  claim 26  further comprising the additional step of inducing the degrading of heme in said mammal with said heme oxygenase to endogenously produce bile pigment and carbon monoxide.  
   
   
       32 . The method of  claim 31  further comprising the additional step of modulating guanylyl cyclase in said mammal with said endogenously produced carbon monoxide.  
   
   
       33 . The method of  claim 31  further comprising the additional step of neutralizing or sequestering free radicals in said mammal with said endogenously produced bile pigment.  
   
   
       34 . The method of  claim 31  further comprising the additional step of inducing a reduction in the blood pressure of said mammal with said endogenously produced carbon monoxide.