NO signaling can be cGMP-dependent or cGMP independent, the latter not involving activation of soluble (or NO-sensitive) guanylyl cyclase (sGC). NO signaling in drug discovery has been dominated by the early association of NO and nitrovasodilators with smooth muscle relaxation in the vasculature and hence cardiovascular, cardiopulmonary, and coronary indications. The prostaglandin-like effects of NO in the GI tract have also infiltrated mainstream thinking for gastroprotective prodrugs. Similarly, NO toxicity resulting from upregulation of inducible nitric oxide synthase (NOS2) and neurotoxicity putatively caused by the corybantic interplay of glutamate and NOS1 have influenced thinking on whether to inhibit or supplement NO in therapy. Firstly, examples will be presented on the use of NO-donor drugs in the less studied vista of NO/cGMP in the CNS: 1) NO-chimeras that reduce levels of neurotoxic amyloid-� (A�) and restore cognition in Alzheimer's animal models; 2) hybird nitrate NO-SSRI's that speculatively may have no therapeutic lag; 3) hybrid NO-flurbils that stimulate A� clearance; and 4) neuroprotective peptidomimetic furoxans. Stimulation of NOS3 by estrogens will be compared with NO-SERMs, chimeric selective estrogen receptor modulators that are procognitive and anti-thrombotic even in the presence of attenuated NOS3 function associated with aging. Secondly, comparison will be made between NO-donor strategies and the use of novel, brain-bioavailable, NO-independent sGC activators and inhibitors in the CNS. Finally, we will remind ourselves that NO-donor bioactivation and bioactivity remains poorly understood, by reference to the biology and forgotten chemistry of aspirin hybrid nitrates that have been pursued in cancer therapy and chemoprevention.

Overview of the nitric oxide pathway in drug discovery in the CNS and periphery

245th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.