Optimization Of The PSD95-nNOS Inhibitors And Their Analgesia Reaction

Over one-third of the world's population suffers from persistent or recurrent pain,costing the American public alone approximately $100 billion each year in health care,compensation,and litigation.Chronic pain is associated with conditions such as back injury,migraine headaches,arthritis,herpes zoster,diabetic neuropathy,temporomandibular joint syndrome,and cancer.Many of the currently available pain therapies are either inadequate or cause uncomfortable to deleterious side effects.Chronic pain results not just from the physical insult but also from a combination of physical,emotional,psychological,and social abnormalities.Because many pains persist after an insult is healed,the ongoing-pain rather than the injury underlies the patient's disability.Untreated pain may become self-perpetuating because pain has immunosuppressive effects that leave patients susceptible to subsequent diseases.It is now clear that if we can effectively treat the pain despite the underlying cause,it will be possible for patients to regain normal functioning.A novel approach to pain therapy is to disrupt the PSD95-nNOS interaction of the NMDA-PSD95-nNOS signalling pathway.This would allow for specific inhibition of the NMDA-nNOS signaling pathway,without blocking NMDA-dependent,but nNOS-independent signalling,thereby sparing unwanted effects on many other important physiological processes mediated by the NMDA receptors.Inhibitors of the PSD95-nNOS protein-protein interaction our lab synthesized before can only demonstrate action by intravenous injection or intrathecal delivery because its low BBB permiting.This will bring inconveniernce and intolerance to the patients.Here after optimizing the structure of the inhibitors,we achieve some compounds,some of these(MT-3,MT-4)can make sense by oral drug administration.