The neurotransmitter acetylcholine mediates a variety of responses within the central nervous system and plays an important role in memory function and cognition. The cholinergic cells within the basal nucleus degenerate in Alzheimer's Disease (AD), a disorder that is associated with memory dysfunction and progressive cognitive decline. Current therapeutic approaches for AD include generalized treatments with agents that increase blood flow to the brain or enhance attention, while more specific strategies focus on increasing levels of acetylcholine or directly simulating cholinergic receptors. The applicants' research efforts have focused on developing selective muscarinic agonists for the treatment of AD. They have identified several active ligands with promising biological activity that serve as lead compounds for the development of novel, selective, and centrally- active muscarinic agonists. This proposal describes the design, synthesis, and biological testing of novel amidine-containing compounds as selective muscarinic agonists. Chemical synthesis will focus on a few key compounds with the aim of improving potency, selectivity and central activity in a series of 1,4,5,6-tetrahydropyrimidine derivatives. Biological testing will seek to identify the molecules with highest affinity and efficacy for m1 muscarinic receptors expressed in cultured cell lines and M1 muscarinic receptors in the hippocampus. In vivo studies will examine the ability for active compounds to penetrate into the brain and reverse memory deficits associated with lesions of the septohippocampal cholinergic system. Structure activity studies will help identify the molecular features which contribute to activity and provide a basis for the rational design and synthesis of new ligands. The overall goal of the proposed studies is to identify a compound with biological activity warranting further development as a drug candidate for the treatment of AD.
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