Novel nitrates as NO mimetics directed at Alzheimer's disease.
GT 1061 is a novel therapeutic agent that is in Phase 1 clinical studies for Alzheimer's disease. GT 1061 is one of a family of novel nitrates that have demonstrated neuroprotective properties and cognition- and memory-enhancing properties in animal models. The prototype of this family, GT 715, has been reported effectively to dissociate the neuromodulatory and the systemic hypotensive effects of nitrates, the latter seriously limiting the therapeutic use of classical nitrates. Further data on the novel nitrates, GT 715 and GT 061, are presented in (a) the malonate-lesion rat model of excitotoxic neurodegeneration, and (b) the reversal of a scopolamine-induced cognition deficit in the Morris water task which tests spatial memory. These data exemplify and reinforce the combined neuroprotective and cognition enhancing properties observed in this family of NO mimetic therapeutic agents. NO mimetics, that mimic the biological activity of NO, will bypass cholinergic receptor activation and are anticipated to provide multiple pathways of treating and circumventing dementia. NO mimetic activation of soluble guanylyl cyclase and cGMP formation in the brain represents one element of an effective neuroprotective strategy. Substantial evidence suggests that NO mimetics may display cGMP-dependent and cGMP-independent activity and may operate via multiple biochemical signaling pathways, both to ensure the survival of neurons subjected to stress and also to provide cognition-enabling pathways to circumvent dementia, providing a combined neuroprotective and cognition-enabling approach to anti-neurodegenerative therapy.
Thatcher
Gregory R J
GR
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. Chicago, IL 60612-7231, USA. thatcher@uic.edu
Bennett
Brian M
BM
Dringenberg
Hans C
HC
Reynolds
James N
JN
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D040761:Biomimetic Materials / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis; D002470:Cell Survival / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009566:Nitrates / Q000494:pharmacology / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000008:administration & dosage / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects; D013028:Space Perception / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects
D002352:Carrier Proteins; C501053:GT 061; C420322:GT 715; D047908:Intracellular Signaling Peptides and Proteins; D018727:Muscarinic Antagonists; D018696:Neuroprotective Agents; D009566:Nitrates; C022994:cyclic GMP-binding protein; D009569:Nitric Oxide; D012601:Scopolamine; D011407:Propane