Alzheimer's disease is a neurodegenerative disorder that accounts for the majority of dementia cases in the modern world. It manifests as a decline in cognitive functions, most notably as long-term and short-term memory loss, accompanied by other impairments in higher brain functions and psychiatric disturbances. The final clinical outcome is a complete dependence on others, and suffering for both the patient and their caregivers. Historically, pharmacotherapy has been limited to cholinesterase inhibitors and NMDA receptor antagonists, and later supplemented by anti-amyloid monoclonal antibodies. However, targeting a single disease mechanism has proven insufficient – current treatments can only slow disease progression rather than stop it. Due to the complex and multifactorial etiopathogenesis of Alzheimer’s disease, drug discovery trends are shifting toward multi-target (multifunctional) ligands.
In this master's thesis, we focused on the design and synthesis of multifunctional cholinesterase inhibitors endowed with additional activity at α7 nicotinic or M1 muscarinic cholinergic receptors, or at α2 adrenergic receptors. The final pleiotropic prodrugs were obtained by combining functional groups known to covalently inhibit cholinesterases (carbamates, phosphates, and carbamoyl fluorides) with known ligands of the abovementioned receptors. The inhibitory potencies of the synthesised compounds against cholinesterases was determined in a biochemical assay. We observed that irreversible inhibitors 14 and 21 are potent cholinesterase inhibitors, whereas selectivity is governed primarily by molecular size – bulkier derivatives selectively inhibit human butyrylcholinesterase (hBChE), and to a lesser extent, acetylcholinesterase. This size-selectivity relationship enables the incorporation of pharmacophores characteristic of the target receptors while simultaneously ensuring the desired selectivity toward hBChE. Accordingly, by suitable modifications of the central core in the design of new analogues, selectivity between the two cholinesterases can be achieved while also conferring activity at the target receptors. A notable example is compound 6, which, in addition to carbamate fragment, features a central scaffold whose size confers selectivity between the cholinesterases and is structurally very similar to atipamezole, a known selective α2-adrenergic receptor antagonist.
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