DESIGN, SYNTHETIC APPROACHES, BIOPHARMACOLOGICAL INVESTIGATION, AND STRUCTURE ACTIVITY RELATIONSHIPS OF NOVEL LIGANDS TARGETING NEURONAL NICOTINIC RECEPTOR SUBTYPES
Tesi di Dottorato
Data di Pubblicazione:
2013
Citazione:
DESIGN, SYNTHETIC APPROACHES, BIOPHARMACOLOGICAL INVESTIGATION, AND STRUCTURE ACTIVITY RELATIONSHIPS OF NOVEL LIGANDS TARGETING NEURONAL NICOTINIC RECEPTOR SUBTYPES / D.y. Pome' ; supervisor: M. De Amici. UNIVERSITA' DEGLI STUDI DI MILANO, 2013 Feb 22. 25. ciclo, Anno Accademico 2012. [10.13130/pome-diego-yuri_phd2013-02-22].
Abstract:
In the central nervous system (CNS), ligand-gated ion channels can be found presynaptically, in nerve terminals, where they control neurotransmitter release. Among them, neuronal nicotinic acetylcholine receptors (nAChRs) constitute a particular example, since nAChR-mediated stimulation of neurotransmitter release is more pronounced than the relatively low numbers of nAChRs might predict. Accordingly, this signal amplification has been hypothesized as the main function of nAChRs in the brain. Thus, nAChRs were found to exert mostly a modulatory role in the CNS, in contrast to that displayed in neuromuscular junctions and autonomic ganglia, where they mediate postsynaptic, fast, excitatory neurotransmission.
Neuronal nAChRs are pentameric combinations of α and α/β subunits, with a high degree of complexity conferred by 12 different α (α2-α10) and β (β2-β4) subunits. Hence, a large repertoire of molecular architectures can be generated, and the functional relevance of these subunit compositions has yet to be fully clarified. Although neuronal nAChRs play an array of critical roles in the central nervous system (CNS), only in the last two decades a rapidly growing understanding of subtype localization has been associated with potential therapeutic applications. Indeed, the most abundant nAChR subtypes in the CNS are α4β2* heteromers, belonging to the group of α-bungarotoxin-insensitive subtypes, and α7 homomers, which are α-bungarotoxin-sensitive receptors. Functionally, α7 channels are distinguished from α4β2-containing receptors mainly for their lower affinity for acetylcholine and their relatively higher permeability to calcium. Even though the α4β2* and α7 subtypes are differently distributed in the CNS, both are expressed in brain regions (cortex, hippocampus) that are involved in cognitive processes, through the modulation of the release of neurotransmitters (besides acetylcholine, glutamate, GABA, dopamine, and serotonin) that control an array of CNS functions. Recently, much attention has been paid to the ganglionic α3β4* receptor subtype, which, owing to its CNS expression in the medial habenula and in the interpeduncolar nucleus, participates to the regulation of dopamine levels in the mesolimbic area.
The improved knowledge of the role played by α4β2*, α7 and α3β4* subtypes in cognitive processes (attention, memory), mood, nociception, and neuroprotection has encouraged the development of subtype-selective compounds designed for different pathologies of the CNS, including Alzheimer’s and Parkinson’s diseases, attention deficit hyperactivity disorder (ADHD), schizophrenia, epilepsy, Tourette’s syndrome, anxiety, depression, pain, and nicotine addiction. In brief, central α7 nAChRs, rapidly opening and rapidly desensitizing ion channels, are implicated in learning, memory, and information processing, including gating deficits that are common in schizophrenia. Conversely, peripheral α7 nAChRs have been shown to play a role in the inflammation response. Central α4β2* nAChRs have been identified as key mediators of the analgesic effects of nicotine agonists, but they are also involved in learning, memory and attention-related effects. On the other hand, the habenular α3β4* subtype is considered a potential novel target for the treatment of nicotine and other drugs addiction as well as of ethanol abuse disorders. However, the involvement of α3β4* receptors in the reward circuit it is far from being completely understood. It has been proposed that α3β4* channels mediate the lateral habenular glutamatergic pathway which is directly linked with the ventrategmental area of the mesolimbic dopamine system. The habenular region, by tuning the dopamine release, could contribute to modulatin
Tipologia IRIS:
Tesi di dottorato
Keywords:
nicotinic receptors ; medicinal chemistry
Elenco autori:
D.Y. Pome'
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