Why aren't neuronal Nitric oxide inhibitors used in humans

[Neuroprotection]

Nitric oxide is an important gassius neurotransmitter and neuromodulater, as well as one of the main down stream affectors of NMDAr activation. Its also a key free radical implicated in neurodegeneration and neuropathology, particularly psychitsaphrenia and depression. The NOS1 enzyme generates nitric oxide in neurons in response to calcium imflux into the cell through NMDA channels.
Spesific NOS1 inhibitors including 7 Nitroindizole and methylene blue have been shown to have various benefits I will list below:
Block or reduce excitotoxicity of glutamate and other toxic aminoacids, both exogenous and endogenous.
Prevent opioid withdrawls in anmils and cultured human neuronal cells, as well as block tolerance development to opioids and even reverce it. Also NOS1 inhibition possibley reverces long term adaptations that often leave former addicts at risk of relaps.
Greatly reduce methamphetamine and other stimulants neurotoxicity and prevents/reverses tolerance.
Have potent anxiolytic and antipsychotic affects without typical side affects seen with benzodiazepines and dopamine antagonists.
Drastically reduce benzodiazepine withdrawl symptoms, block seizures associated with withdrawal as well as epilepsy, and over time eliminates tolerance to benzodiazepines and all other gabaAergics. NOS1 inhibitors also reduce propofol and other anaesthetic requirement to produce deap unconsciousness.
Have powerfull antidepressant affects.
Are potent neuroprotective agents in animals.

Given all these benefits, why an’t potent NOS1 inhibitors particularly 7 nitroindizole used in humans. Are there any sideaffects or obstacles prevent drug development

 

[serotonin2A]

I think your post inadvertantly answers your question. The fact that NO is involved in so many processes makes NOS a difficult target.

There are some NO drugs used, for example nitroglycerin and sildenafil. But sildenafil is a good evample of why NO is a tough target. Sildenafil is a useful drug because there are many PDE enzymes, so inhibitors can be developed that target one particular function. But even with a selective drug like sildenafil, there are some hints of unselective effects, hence why people sometimes go blind after taking it.

 

[Neuroprotection]

Thanks for your response
What you referred to as NO drugs increase nitric oxide production or its downstream effects, conversely NOS1 inhibitors should only block nitric oxide production in neurons. I understand your concept of unselectivity, but I would be interested to know if you or any one else knew what the side effects of specifically blocking nitric oxide production in neurons?

 

[serotonin2A]

Interesting, don't know much about this pathway but ran into it when researching about the K related bladder issues - so there is a direct connection between NMDARs and NO or its enzymes?

NO is a second messenger downstream from NMDA-R. Very useful for retrograde signaling because it can diffuse across membranes.

 

[Cotcha Yankinov]

Bump, thought I would post that minocycline appears to inhibit inducible nitric oxide synthase http://www.ncbi.nlm.nih.gov/m/pubmed/11246672/

I read about it in a couple other studies as well that were investigating minocycline's utility. Very interesting compound, appears to have use in most inflammatory/auto immune conditions.

 

[asecin]

I think your post inadvertantly answers your question. The fact that NO is involved in so many processes makes NOS a difficult target.

There are some NO drugs used, for example nitroglycerin and sildenafil. But sildenafil is a good evample of why NO is a tough target. Sildenafil is a useful drug because there are many PDE enzymes, so inhibitors can be developed that target one particular function. But even with a selective drug like sildenafil, there are some hints of unselective effects, hence why people sometimes go blind after taking it.

people went blind after taking sildenafil? was that one of those temporary losses of sight which concludes the sex act...

 

[serotonin2A]

people went blind after taking sildenafil? was that one of those temporary losses of sight which concludes the sex act...

No, it is a permenant loss of sight when blood flow to the optic nerve gets cut off.

It is rare, and usually temporary, but vision does not always recover.