The utility of muscarinic agonists in the treatment of Alzheimer's disease.
Alzheimer's disease is a progressive neurological disorder characterized by amyloid plaques and neurofibrillary tangles along with memory and cognitive deficits associated with a loss of basal forebrain cholinergic neurons. Efforts to treat Alzheimer's disease have focused on compounds that elevate cholinergic activity such as cholinesterase inhibitors and direct acting muscarinic and nicotinic agonists. Low efficacy and poor selectivity of available compounds have limited the clinical utility of muscarinic agonists. Recent studies suggesting a role for muscarinic agonists in regulating the production of A beta raise the possibility that selective M1 agonists could be useful in treating not only the symptoms, but also the underlying cause(s) of Alzheimer's disease. Thus, renewed efforts have focused on the development of compounds with improved selectivity for M1 receptors and lower toxicity. 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine (CDD-0102) is a potent M1 agonist with a low side effect profile that enhances memory function in animal models of Alzheimer's disease. The available preclinical data suggest that CDD-0102 may be useful in the treatment of Alzheimer's disease.
Messer
William S
WS
Department of Pharmacology, College of Pharmacy, The University of Toledo, OH 43606, USA. wmesser@utnet.utoledo.edu
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018929:Cell Culture Techniques; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D008568:Memory / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013830:Thiadiazoles; D002217:Carbachol; C075257:xanomeline; D002795:Choline O-Acetyltransferase