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Abstract
The development of small molecule modulators of NO/cGMP signaling for use in the CNS
has lagged far behind the use of such clinical agents in the periphery, despite the
central role played by NO/cGMP in learning and memory, and the substantial evidence
that this signaling pathway is perturbed in neurodegenerative disorders, including
Alzheimer's disease. The NO-chimeras, NMZ and Nitrosynapsin, have yielded beneficial
and disease-modifying responses in multiple preclinical animal models, acting on GABAA
and NMDA receptors, respectively, providing additional mechanisms of action relevant
to synaptic and neuronal dysfunction. Several inhibitors of cGMP-specific phosphodiesterases
(PDE) have replicated some of the actions of these NO-chimeras in the CNS. There is
no evidence that nitrate tolerance is a phenomenon relevant to the CNS actions of
NO-chimeras, and studies on nitroglycerin in the periphery continue to challenge the
dogma of nitrate tolerance mechanisms. Hybrid nitrates have shown much promise in
the periphery and CNS, but to date only one treatment has received FDA approval, for
glaucoma. The potential for allosteric modulation of soluble guanylate cyclase (sGC)
in brain disorders has not yet been fully explored nor exploited; whereas multiple
applications of PDE inhibitors have been explored and many have stalled in clinical
trials.