title: Neurochemistry of aging. 1. Toxins for an animal model of Alzheimer's disease.
abstract: A chronic deficiency in central cholinergic function has been implicated in a number of neuropsychiatric diseases including Alzheimer's disease. Until recently, animal models that simulate the neurochemical conditions that appear to cause these diseases in humans, as a result of a direct manipulation of the central cholinergic system, were not available. Over the past few years, however, we have been successful in developing a cholinotoxin, 1-ethyl-1-(2-hydroxyethyl)aziridinium chloride (AF64A), which has the potential to serve as a novel compound in developing animal models of human brain disorders in which a cholinergic hypofunction has been implicated. In this paper are described the design, synthesis, and testing of several structural analogues of AF64A as potential cholinotoxins, by evaluating them for their ability to inhibit high-affinity choline transport and their affinity toward brain muscarinic receptors. One of the compounds, 1-cyclopropyl-1-(2-hydroxyethyl)aziridinium chloride (i.e. aziridine analogue of 13) was found to have a remarkably high affinity (about 40 times higher than AF64A) toward brain muscarinic receptors.
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced* / Q000378:metabolism; D000818:Animals; D001388:Aziridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001389:Azirines / Q000138:chemical synthesis*; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002794:Choline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D014118:Toxins, Biological / Q000138:chemical synthesis* / Q000378:metabolism
chemical_list: D001388:Aziridines; D001389:Azirines; D011976:Receptors, Muscarinic; D014118:Toxins, Biological; D011813:Quinuclidinyl Benzilate; C044894:ethylcholine aziridinium; D002794:Choline